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1. Urine-based multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Author: Richa Batra, Rie Uni, Oleh M. Akchurin, Sergio Alvarez-Mulett, Luis G. Gómez-Escobar, Edwin Patino, Katherine L. Hoffman, Will Simmons, William Whalen, Kelsey Chetnik, Mustafa Buyukozkan, Elisa Benedetti, Karsten Suhre, Edward Schenck, Soo Jung Cho, Augustine M. K. Choi, Frank Schmidt, Mary E. Choi, and Jan Krumsiek
Subjects: COVID-19, Acute respiratory distress syndrome (ARDS), Multi-omic, Mortality signature, Network-based, Computational analysis, Therapeutics. Pharmacology, RM1-950, Biochemistry, QD415-436
Abstract: Abstract Background Acute respiratory distress syndrome (ARDS), a life-threatening condition during critical illness, is a common complication of COVID-19. It can originate from various disease etiologies, including severe infections, major injury, or inhalation of irritants. ARDS poses substantial clinical challenges due to a lack of etiology-specific therapies, multisystem involvement, and heterogeneous, poor patient outcomes. A molecular comparison of ARDS groups holds the potential to reveal common and distinct mechanisms underlying ARDS pathogenesis. Methods We performed a comparative analysis of urine-based metabolomics and proteomics profiles from COVID-19 ARDS patients (n = 42) and bacterial sepsis-induced ARDS patients (n = 17). To this end, we used two different approaches, first we compared the molecular omics profiles between ARDS groups, and second, we correlated clinical manifestations within each group with the omics profiles. Results The comparison of the two ARDS etiologies identified 150 metabolites and 70 proteins that were differentially abundant between the two groups. Based on these findings, we interrogated the interplay of cell adhesion/extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis through a multi-omic network approach. Moreover, we identified a proteomic signature associated with mortality in COVID-19 ARDS patients, which contained several proteins that had previously been implicated in clinical manifestations frequently linked with ARDS pathogenesis. Conclusion In summary, our results provide evidence for significant molecular differences in ARDS patients from different etiologies and a potential synergy of extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis. The proteomic mortality signature should be further investigated in future studies to develop prediction models for COVID-19 patient outcomes.
Published: 2023
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2. Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Author: Richa Batra, William Whalen, Sergio Alvarez-Mulett, Luis G. Gomez-Escobar, Katherine L. Hoffman, Will Simmons, John Harrington, Kelsey Chetnik, Mustafa Buyukozkan, Elisa Benedetti, Mary E. Choi, Karsten Suhre, Edward Schenck, Augustine M. K. Choi, Frank Schmidt, Soo Jung Cho, and Jan Krumsiek
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Background Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions. Methods and findings In this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation. Conclusion We present a first comprehensive molecular characterization of differences between two ARDS etiologies–COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions. Author summary Acute respiratory distress syndrome (ARDS) is a critical condition of the lung that can arise after severe infections, traumatic injury, or inhalation of toxins. Patients with ARDS are in a complex disease state and at risk of multiple clinical complications, such as thrombosis, lung fibrosis, acute kidney injury, and increased mortality. Currently, there are substantial challenges in the treatment of ARDS due to the high heterogeneity of this condition across patients. Our study compared metabolomic and proteomic changes induced by two different causes of ARDS—COVID-19 infection and bacterial sepsis. We used blood samples of patients from each ARDS group for molecular profiling and identified several hundred molecules from various biological processes differing between the two groups. Based on these results, we made several new propositions: (1) A role of arginine metabolism in long-term sequelae of ARDS. (2) The potential use of JAK-STAT pathway inhibitors for bacterial sepsis-induced ARDS. (3) ARDS-associated mitochondrial dysfunction as a reason for poor prognosis of acute kidney injury that occurred during ARDS. (4) A synergy between prothrombotic processes as a potential reason for hypercoagulation in ARDS. We hypothesize that combination therapy targeting two or more of these prothrombotic processes may ameliorate hypercoagulation.
Published: 2022

3. Modulation of the Association Between Age and Death by Risk Factor Burden in Critically Ill Patients With COVID-19

Author: Ashwin Sunderraj, BS, Chloe Cho, Xuan Cai, MS, Shruti Gupta, MD, MPH, Rupal Mehta, MD, MSCI, Tamara Isakova, MD, MMSc, David E. Leaf, MD, MMSc, Anand Srivastava, MD, MPH, STOP-COVID Investigators, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Shristi Upadhyay, Ishaan Vohra, Ajiboye Oyintayo, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, Aquino Williams, Samantha K. Brenner, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Miguel A. Hernán, Amy M. Zhou, Ethan C. Kim, Rebecca Lisk, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Pattharawin Pattharanitima, Emily J. Gallagher, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, Samir C. Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddhartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Dheeraj Reddy Sirganagari, Pramod K. Guru, Kianoush Kashani, Shahrzad Tehranian, Yan Zhou, Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Michal L. Melamed, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Neelja Kumar, Michael Chang, Jyotsana Thakkar, Ritesh Raichoudhury, Akshay Athreya, Mohamed Farag, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Sobaata Chaudhry, Benjamin Wu, Frank Modersitzki, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner MB. Mohamed, Rupali S. Avasare, David Zonies, David E. Leaf, Shruti Gupta, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Ariel L. Mueller, Roberta E. Redfern, Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, Laura Bickley, Chris Rowan, Farah Madhani-Lovely, Vivian S. Cruz, Kristen M. Hess, Alanna L. Jacobs, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, Mark Liotta, Jared Radbel, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth S. Vatson, Shuchi Anand, Joseph E. Levitt, Pablo Garcia, Suzanne M. Boyle, Rui Song, Jingjing Zhang, Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, Katharine Senter, Moh’d A. Sharshir, Vadym V. Rusnak, Muhammad Imran Ali, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, David J. Douin, Arash Rashidi, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Carl E. Schulze, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Madona Elias, Yahya Ahmad, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Hayley B. Gershengorn, Bhavarth Shukla, Alessia Fornoni, Tanira Ferreira, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’ Hayer, Chelsea Meloche, Rafey Feroze, Rayan Kaakati, Danny Perry, Abbas Bitar, Elizabeth Anderson, Kishan J. Padalia, John P. Donnelly, Andrew J. Admon, Jennifer E. Flythe, Matthew J. Tugman, Emily H. Chang, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, Huiwen Chen, Csaba P. Kovesdy, Miklos Z. Molnar, Ambreen Azhar, S. Susan Hedayati, Mridula V. Nadamuni, Shani Shastri, Duwayne L. Willett, Samuel A.P. Short, Amanda D. Renaghan, Kyle B. Enfield, Pavan K. Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Nitender Goyal, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Ravi K. Kshirsagar, Daniel E. Weiner, Aju Jose, Marta Christov, Jennifer Griffiths, Sanjeev Gupta, Aromma Kapoor, Perry Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: OBJECTIVES:. Older age is a key risk factor for adverse outcomes in critically ill patients with COVID-19. However, few studies have investigated whether preexisting comorbidities and acute physiologic ICU factors modify the association between age and death. DESIGN:. Multicenter cohort study. SETTING:. ICUs at 68 hospitals across the United States. PATIENTS:. A total of 5,037 critically ill adults with COVID-19 admitted to ICUs between March 1, 2020, and July 1, 2020. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The primary exposure was age, modeled as a continuous variable. The primary outcome was 28-day inhospital mortality. Multivariable logistic regression tested the association between age and death. Effect modification by the number of risk factors was assessed through a multiplicative interaction term in the logistic regression model. Among the 5,037 patients included (mean age, 60.9 yr [± 14.7], 3,179 [63.1%] male), 1,786 (35.4%) died within 28 days. Age had a nonlinear association with 28-day mortality (p for nonlinearity
Published: 2022
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4. Cytokine signatures of end organ injury in COVID-19

Author: Luis G. Gómez-Escobar, Katherine L. Hoffman, Justin J. Choi, Alain Borczuk, Steven Salvatore, Sergio L. Alvarez-Mulett, Manuel D. Galvan, Zhen Zhao, Sabrina E. Racine-Brzostek, He S. Yang, Heather W. Stout-Delgado, Mary E. Choi, Augustine M. K. Choi, Soo Jung Cho, and Edward J. Schenck
Subjects: Medicine, Science
Abstract: Abstract Increasing evidence has shown that Coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunologic response. We aimed to assess the differences in inflammatory cytokines in COVID-19 patients compared to contemporaneously hospitalized controls and then analyze the relationship between these cytokines and the development of Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI) and mortality. In this cohort study of hospitalized patients, done between March third, 2020 and April first, 2020 at a quaternary referral center in New York City we included adult hospitalized patients with COVID-19 and negative controls. Serum specimens were obtained on the first, second, and third hospital day and cytokines were measured by Luminex. Autopsies of nine cohort patients were examined. We identified 90 COVID-19 patients and 51 controls. Analysis of 48 inflammatory cytokines revealed upregulation of macrophage induced chemokines, T-cell related interleukines and stromal cell producing cytokines in COVID-19 patients compared to the controls. Moreover, distinctive cytokine signatures predicted the development of ARDS, AKI and mortality in COVID-19 patients. Specifically, macrophage-associated cytokines predicted ARDS, T cell immunity related cytokines predicted AKI and mortality was associated with cytokines of activated immune pathways, of which IL-13 was universally correlated with ARDS, AKI and mortality. Histopathological examination of the autopsies showed diffuse alveolar damage with significant mononuclear inflammatory cell infiltration. Additionally, the kidneys demonstrated glomerular sclerosis, tubulointerstitial lymphocyte infiltration and cortical and medullary atrophy. These patterns of cytokine expression offer insight into the pathogenesis of COVID-19 disease, its severity, and subsequent lung and kidney injury suggesting more targeted treatment strategies.
Published: 2021
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5. Integrative metabolomic and proteomic signatures define clinical outcomes in severe COVID-19

Author: Mustafa Buyukozkan, Sergio Alvarez-Mulett, Alexandra C. Racanelli, Frank Schmidt, Richa Batra, Katherine L. Hoffman, Hina Sarwath, Rudolf Engelke, Luis Gomez-Escobar, Will Simmons, Elisa Benedetti, Kelsey Chetnik, Guoan Zhang, Edward Schenck, Karsten Suhre, Justin J. Choi, Zhen Zhao, Sabrina Racine-Brzostek, He S. Yang, Mary E. Choi, Augustine M.K. Choi, Soo Jung Cho, and Jan Krumsiek
Subjects: Biological sciences, Clinical finding, Human metabolism, Medicine, Physiology, Science
Abstract: Summary: The coronavirus disease-19 (COVID-19) pandemic has ravaged global healthcare with previously unseen levels of morbidity and mortality. In this study, we performed large-scale integrative multi-omics analyses of serum obtained from COVID-19 patients with the goal of uncovering novel pathogenic complexities of this disease and identifying molecular signatures that predict clinical outcomes. We assembled a network of protein-metabolite interactions through targeted metabolomic and proteomic profiling in 330 COVID-19 patients compared to 97 non-COVID, hospitalized controls. Our network identified distinct protein-metabolite cross talk related to immune modulation, energy and nucleotide metabolism, vascular homeostasis, and collagen catabolism. Additionally, our data linked multiple proteins and metabolites to clinical indices associated with long-term mortality and morbidity. Finally, we developed a novel composite outcome measure for COVID-19 disease severity based on metabolomics data. The model predicts severe disease with a concordance index of around 0.69, and shows high predictive power of 0.83–0.93 in two independent datasets.
Published: 2022
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6. Impact of Senolytic Treatment on Gene Expression in Aged Lung

Author: Soo Jung Cho, Alexander Pronko, Jianjun Yang, and Heather Stout-Delgado
Subjects: senescence, lung, senolytics, chronic inflammation, aging, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Cellular senescence plays a key role in mediating tissue remodeling and modulation of host responses to pathogenic stimuli. Our current study was designed to gain a better understanding of the impact of short-term senolytic treatment or inflammatory stimulation on lung senescence. The results of our study demonstrate that short term treatment of aged adult mice (20 months of age) with senolytics, quercetin, and dasatinib decreases p16 and p21 expression in lung tissue. Short-term treatment with senolytics also significantly improved the expression of genes associated with genomic instability, telomere attrition, mitochondrial dysfunction, DNA binding, and the inflammatory response. In contrast, in response to low-dose LPS administration, there was increased expression of genes associated with genomic instability, mitochondrial dysfunction, and heightened inflammatory responses in young adult murine lung (3 months of age). Taken together, the results of our current study illustrate the efficacy of senolytic treatment on modulating responses in aged lung and the potential role of chronic low dose inflammation on senescence induction in the lung.
Published: 2023
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7. Role of Cholesterol 25-Hydroxylase (Ch25h) in Mediating Innate Immune Responses to Streptococcus pneumoniae Infection

Author: Soo Jung Cho, Alexander Pronko, Jianjun Yang, Kassandra Pagan, and Heather Stout-Delgado
Subjects: Streptococcus pneumoniae, Ch25h, alveolar macrophage, Cytology, QH573-671
Abstract: Alveolar macrophages (AM) are long-lived tissue-resident innate immune cells of the airways. AM are key effectors of recognition, initiation, and resolution of the host defense against microbes and play an essential role in mediating host responses to Streptococcus pneumoniae infection. Lipid metabolism in AM can significantly impact cellular function and biology. Dysregulated metabolism contributes to an accumulation of lipids, unfolded protein response induction, and inflammatory cytokine production. Our study was designed to investigate the impact of Ch25h on mediating innate immune responses by macrophages during S. pneumoniae infection. Using wild-type and Ch25−/− mice, we examined the role of cholesterol metabolism on inflammatory cytokine production and bacterial clearance. Our results demonstrate that Ch25h plays an important role in the initiation and intensity of cytokine and chemokine production in the lung during S. pneumoniae infection. In the absence of Ch25h, there was enhanced phagocytosis and bacterial clearance. Taken together, our findings demonstrate the important role of Ch25h in modulating host responsiveness to S. pneumoniae infection.
Published: 2023
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8. Identification of Robust Protein Associations With COVID-19 Disease Based on Five Clinical Studies

Author: Karsten Suhre, Hina Sarwath, Rudolf Engelke, Muhammad Umar Sohail, Soo Jung Cho, William Whalen, Sergio Alvarez-Mulett, Jan Krumsiek, Augustine M. K. Choi, and Frank Schmidt
Subjects: COVID-19, Olink proteomics, inflammation and cardiovascular markers, cytokine storm syndrome, CCL16, CXCL10, Immunologic diseases. Allergy, RC581-607
Abstract: Multiple studies have investigated the role of blood circulating proteins in COVID-19 disease using the Olink affinity proteomics platform. However, study inclusion criteria and sample collection conditions varied between studies, leading to sometimes incongruent associations. To identify the most robust protein markers of the disease and the underlying pathways that are relevant under all conditions, it is essential to identify proteins that replicate most widely. Here we combined the Olink proteomics profiles of two newly recruited COVID-19 studies (N=68 and N=98) with those of three previously published COVID-19 studies (N=383, N=83, N=57). For these studies, three Olink panels (Inflammation and Cardiovascular II & III) with 253 unique proteins were compared. Case/control analysis revealed thirteen proteins (CCL16, CCL7, CXCL10, CCL8, LGALS9, CXCL11, IL1RN, CCL2, CD274, IL6, IL18, MERTK, IFNγ, and IL18R1) that were differentially expressed in COVID-19 patients in all five studies. Except CCL16, which was higher in controls, all proteins were overexpressed in COVID-19 patients. Pathway analysis revealed concordant trends across all studies with pathways related to cytokine-cytokine interaction, IL18 signaling, fluid shear stress and rheumatoid arthritis. Our results reaffirm previous findings related to a COVID-19 cytokine storm syndrome. Cross-study robustness of COVID-19 specific protein expression profiles support the utility of affinity proteomics as a tool and for the identification of potential therapeutic targets.
Published: 2022
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9. Performance of crisis standards of care guidelines in a cohort of critically ill COVID-19 patients in the United States

Author: Julia L. Jezmir, Maheetha Bharadwaj, Alexander Chaitoff, Bradford Diephuis, Conor P. Crowley, Sandeep P. Kishore, Eric Goralnick, Louis T. Merriam, Aimee Milliken, Chanu Rhee, Nicholas Sadovnikoff, Sejal B. Shah, Shruti Gupta, David E. Leaf, William B. Feldman, Edy Y. Kim, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Shristi Upadhyay, Ishaan Vohra, Ajiboye Oyintayo, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, Aquino Williams, Samantha K. Brenner, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Miguel A. Hernán, Amy M. Zhou, Ethan C. Kim, Rebecca Lisk, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Pattharawin Pattharanitima, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Elena Cervantes, Samir Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Dheeraj Reddy Sirganagari, Pramod K. Guru, Kianoush Kashani, Yan Zhou, Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Michal L. Melamed, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Neelja Kumar, Michael Chang, Ritesh Raichoudhury, Akshay Athreya, Mohamed Farag, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Sobaata Chaudhry, Benjamin Wu, Frank Modersitzki, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner MB. Mohamed, Rupali S. Avasare, David Zonies, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Ariel L. Mueller, Roberta Redfern, Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, Laura Bickley, Chris Rowan, Farah Madhani-Lovely, Vivian S. Cruz, Kristen M. Hess, Alanna L. Jacobs, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, Mark Liotta, Jared Radbel, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth S. Vatson, Shuchi Anand, Joseph E. Levitt, Suzanne M. Boyle, Rui Song, Jingjing Zhang, Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, Katharine Senter, Moh’d A. Sharshir, Vadym V. Rusnak, Muhammad Imran Ali, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Arash Rashidi, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Madona Elias, Yahya Ahmad, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Hayley B. Gershengorn, Bhavarth Shukla, Alessia Fornoni, Tanira Ferreira, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’ Hayer, Chelsea Meloche, Rafey Feroze, Rayan Kaakati, Danny Perry, Abbas Bitar, Elizabeth Anderson, Kishan J. Padalia, John P. Donnelly, Andrew J. Admon, Jennifer E. Flythe, Matthew J. Tugman, Emily H. Chang, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, Csaba P. Kovesdy, Miklos Z. Molnar, Ambreen Azhar, S. Susan Hedayati, Mridula V. Nadamuni, Shani Shastri, Duwayne L. Willett, Samuel A.P. Short, Amanda D. Renaghan, Kyle B. Enfield, Pavan K. Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Nitender Goyal, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Ravi K. Kshirsagar, Daniel E. Weiner, Aju Jose, Marta Christov, Jennifer Griffiths, Sanjeev Gupta, Aromma Kapoor, Perry Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: medical ethics, crisis standards of care, triage, critical care, intensive care, COVID-19, Medicine (General), R5-920
Abstract: Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.
Published: 2021
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10. Machine Learning Prediction of Death in Critically Ill Patients With Coronavirus Disease 2019

Author: Matthew M. Churpek, MD, MPH, PhD, Shruti Gupta, MD, MPH, Alexandra B. Spicer, MS, Salim S. Hayek, MD, Anand Srivastava, MD, MPH, Lili Chan, MD, MSCR, Michal L. Melamed, MD, MHS, Samantha K. Brenner, MD, MPH, Jared Radbel, MD, Farah Madhani-Lovely, MD, Pavan K. Bhatraju, MD, MSc, Anip Bansal, MD, Adam Green, MD, MBA, Nitender Goyal, MD, Shahzad Shaefi, MD, MPH, Chirag R. Parikh, MD, PhD, Matthew W. Semler, MD, David E. Leaf, MD, MMSc, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, ThuyDuyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Oyintayo Ajiboye, Matthew Itteera, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Metha, Aquino Williams, Samantha K. Brenner, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Miguel A. Hernán, Amy M. Zhou, Ethan C. Kim, Rebecca Lisk, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, Samir C. Gautam, Crystal Chang, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Pramod K. Guru, Paul A. Bergl, Yan Zhou, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Michal L. Melamed, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Jyotsana Thakkar, Neelja Kumar, Michael J. Ross, Michael Chang, Ritesh Raichoudhury, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Daniel W. Ross, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner MB. Mohamed, Rupali S. Avasare, David Zonies, David E. Leaf, Shruti Gupta, Rebecca M. Baron, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa Gaviria, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Saif A. Muhsin, Ernest I. Mandel, Ariel L. Mueller, Nicholas S. Cairl, Farah Madhani-Lovely, Chris Rowan, Farah Madhai-Lovely, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Jared Radbel, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth Vatson, Shuchi Anand, Joseph E. Levitt, Pablo Garcia, Suzanne M. Boyle, Rui Song, Jingjing Zhang, Moh’d A. Sharshir, Vadym V. Rusnak, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Arash Rashidi, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Carl E. Schulze, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Hayley B. Gershengorn, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’ Hayer, Chelsea Meloche, Rafey Feroze, Kishan J. Padalia, Jeff Leya, John P. Donnelly, Andrew J. Admon, Jennifer E. Flythe, Matthew J. Tugman, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Csaba P. Kovesdy, Miklos Z. Molnar, S. Susan Hedayati, Mridula V. Nadamuni, Sadaf S. Khan, Duwayne L. Willett, Samuel A.P. Short, Amanda D. Renaghan, Pavan Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Nitender Goyal, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Marta Christov, Francis P. Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: OBJECTIVES:. Critically ill patients with coronavirus disease 2019 have variable mortality. Risk scores could improve care and be used for prognostic enrichment in trials. We aimed to compare machine learning algorithms and develop a simple tool for predicting 28-day mortality in ICU patients with coronavirus disease 2019. DESIGN:. This was an observational study of adult patients with coronavirus disease 2019. The primary outcome was 28-day inhospital mortality. Machine learning models and a simple tool were derived using variables from the first 48 hours of ICU admission and validated externally in independent sites and temporally with more recent admissions. Models were compared with a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 using the area under the receiver operating characteristic curve and calibration. SETTING:. Sixty-eight U.S. ICUs. PATIENTS:. Adults with coronavirus disease 2019 admitted to 68 ICUs in the United States between March 4, 2020, and June 29, 2020. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The study included 5,075 patients, 1,846 (36.4%) of whom died by day 28. eXtreme Gradient Boosting had the highest area under the receiver operating characteristic curve in external validation (0.81) and was well-calibrated, while k-nearest neighbors were the lowest performing machine learning algorithm (area under the receiver operating characteristic curve 0.69). Findings were similar with temporal validation. The simple tool, which was created using the most important features from the eXtreme Gradient Boosting model, had a significantly higher area under the receiver operating characteristic curve in external validation (0.78) than the Sequential Organ Failure Assessment score (0.69), National Early Warning Score (0.60), and CURB-65 (0.65; p < 0.05 for all comparisons). Age, number of ICU beds, creatinine, lactate, arterial pH, and Pao2/Fio2 ratio were the most important predictors in the eXtreme Gradient Boosting model. CONCLUSIONS:. eXtreme Gradient Boosting had the highest discrimination overall, and our simple tool had higher discrimination than a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 on external validation. These models could be used to improve triage decisions and clinical trial enrichment.
Published: 2021
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11. Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis

Author: Kuei-Pin Chung, Chia-Lang Hsu, Li-Chao Fan, Ziling Huang, Divya Bhatia, Yi-Jung Chen, Shu Hisata, Soo Jung Cho, Kiichi Nakahira, Mitsuru Imamura, Mary E. Choi, Chong-Jen Yu, Suzanne M. Cloonan, and Augustine M. K. Choi
Subjects: Science
Abstract: Mitochondria of alveolar type 2 epithelial cells (AEC2) in the lung have been suggested to play a role in the development of idiopathic pulmonary fibrosis (IPF). Here the authors show that loss of mitofusin1 and mitofusin2 in murine AEC2 cells leads to the development of lung fibrosis through the regulation of surfactant lipids.
Published: 2019
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12. Antiviral Gene Expression in Young and Aged Murine Lung during H1N1 and H3N2

Author: Rebecca Harris, Jianjun Yang, Kassandra Pagan, Soo Jung Cho, and Heather Stout-Delgado
Subjects: antiviral, H3N2, H1N1, influenza, aging, lung, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Influenza is a respiratory virus that alone or in combination with secondary bacterial pathogens can contribute to the development of acute pneumonia in persons >65 years of age. Host innate immune antiviral signaling early in response to influenza is essential to inhibit early viral replication and guide the initiation of adaptive immune responses. Using young adult (3 months) and aged adult mice infected with mouse adapted H1N1 or H3N2, the results of our study illustrate dysregulated and/or diminished activation of key signaling pathways in aged lung contribute to increased lung inflammation and morbidity. Specifically, within the first seven days of infection, there were significant changes in genes associated with TLR and RIG-I signaling detected in aged murine lung in response to H1N1 or H3N2. Taken together, the results of our study expand our current understanding of age-associated changes in antiviral signaling in the lung.
Published: 2021
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13. Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung

Author: Ermias Jirru, Stefi Lee, Rebecca Harris, Jianjun Yang, Soo Jung Cho, and Heather Stout-Delgado
Subjects: aging, viral immune imprinting, influenza, Streptococcus pneumoniae, vaccine effectiveness, Medicine
Abstract: Changes in innate and adaptive immune responses caused by viral imprinting can have a significant direct or indirect influence on secondary infections and vaccine responses. The purpose of our current study was to investigate the role of immune imprinting by influenza on pneumococcal vaccine effectiveness during Streptococcus pneumoniae infection in the aged murine lung. Aged adult (18 months) mice were vaccinated with the pneumococcal polyvalent vaccine Pneumovax (5 mg/mouse). Fourteen days post vaccination, mice were instilled with PBS or influenza A/PR8/34 virus (3.5 × 102 PFU). Control and influenza-infected mice were instilled with PBS or S. pneumoniae (1 × 103 CFU, ATCC 6303) on day 7 of infection and antibacterial immune responses were assessed in the lung. Our results illustrate that, in response to a primary influenza infection, there was diminished bacterial clearance and heightened production of pro-inflammatory cytokines, such as IL6 and IL1β. Vaccination with Pneumovax decreased pro-inflammatory cytokine production by modulating NFҡB expression; however, these responses were significantly diminished after influenza infection. Taken together, the data in our current study illustrate that immune imprinting by influenza diminishes pneumococcal vaccine efficacy and, thereby, may contribute to increased susceptibility of older persons to a secondary infection with S. pneumoniae.
Published: 2020
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14. DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis

Author: Soo Jung Cho, Mihye Lee, Heather W. Stout-Delgado, and Jong-Seok Moon
Subjects: drosha, mirna, aim2 inflammasome, ipf, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Chronic lung inflammation is linked to the pathogenesis of IPF. DROSHA, a class 2 ribonuclease III enzyme, has an important role in the biogenesis of microRNA (miRNA). The function of miRNAs has been identified in the regulation of the target gene or protein related to inflammatory responses via degradation of mRNA or inhibition of translation. The absent-in-melanoma-2 (AIM2) inflammasome is critical for inflammatory responses against cytosolic double stranded DNA (dsDNA) from pathogen-associated molecular patterns (PAMPs) and self-DNA from danger-associated molecular patterns (DAMPs). The AIM2 inflammasome senses double strand DNA (dsDNA) and interacts with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which recruits pro-caspase-1 and regulates the maturation and secretion of interleukin (IL)-1β and IL-18. A recent study showed that inflammasome activation contributes to lung inflammation and fibrogenesis during IPF. In the current review, we discuss recent advances in our understanding of the DROSHA−miRNA−AIM2 inflammasome axis in the pathogenesis of IPF.
Published: 2020
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15. DROSHA-Dependent AIM2 Inflammasome Activation Contributes to Lung Inflammation during Idiopathic Pulmonary Fibrosis

Author: Soo Jung Cho, Kyoung Sook Hong, Ji Hun Jeong, Mihye Lee, Augustine M. K. Choi, Heather W. Stout-Delgado, and Jong-Seok Moon
Subjects: DROSHA, miRNA, AIM2 inflammasome, idiopathic pulmonary fibrosis, Cytology, QH573-671
Abstract: Idiopathic pulmonary fibrosis (IPF) has been linked to chronic lung inflammation. Drosha ribonuclease III (DROSHA), a class 2 ribonuclease III enzyme, plays a key role in microRNA (miRNA) biogenesis. However, the mechanisms by which DROSHA affects the lung inflammation during idiopathic pulmonary fibrosis (IPF) remain unclear. Here, we demonstrate that DROSHA regulates the absent in melanoma 2 (AIM2) inflammasome activation during idiopathic pulmonary fibrosis (IPF). Both DROSHA and AIM2 protein expression were elevated in alveolar macrophages of patients with IPF. We also found that DROSHA and AIM2 protein expression were increased in alveolar macrophages of lung tissues in a mouse model of bleomycin-induced pulmonary fibrosis. DROSHA deficiency suppressed AIM2 inflammasome-dependent caspase-1 activation and interleukin (IL)-1β and IL-18 secretion in primary mouse alveolar macrophages and bone marrow-derived macrophages (BMDMs). Transduction of microRNA (miRNA) increased the formation of the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks, which is required for AIM2 inflammasome activation in BMDMs. Our results suggest that DROSHA promotes AIM2 inflammasome activation-dependent lung inflammation during IPF.
Published: 2019
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16. Comparison of WTC dust size on macrophage inflammatory cytokine release in vivo and in vitro.

Author: Michael D Weiden, Bushra Naveed, Sophia Kwon, Leopoldo N Segal, Soo Jung Cho, Jun Tsukiji, Rohan Kulkarni, Ashley L Comfort, Kusali J Kasturiarachchi, Colette Prophete, Mitchell D Cohen, Lung-Chi Chen, William N Rom, David J Prezant, and Anna Nolan
Subjects: Medicine, Science
Abstract: The WTC collapse exposed over 300,000 people to high concentrations of WTC-PM; particulates up to ∼50 mm were recovered from rescue workers' lungs. Elevated MDC and GM-CSF independently predicted subsequent lung injury in WTC-PM-exposed workers. Our hypotheses are that components of WTC dust strongly induce GM-CSF and MDC in AM; and that these two risk factors are in separate inflammatory pathways.Normal adherent AM from 15 subjects without WTC-exposure were incubated in media alone, LPS 40 ng/mL, or suspensions of WTC-PM(10-53) or WTC-PM(2.5) at concentrations of 10, 50 or 100 µg/mL for 24 hours; supernatants assayed for 39 chemokines/cytokines. In addition, sera from WTC-exposed subjects who developed lung injury were assayed for the same cytokines. In the in vitro studies, cytokines formed two clusters with GM-CSF and MDC as a result of PM(10-53) and PM(2.5). GM-CSF clustered with IL-6 and IL-12(p70) at baseline, after exposure to WTC-PM(10-53) and in sera of WTC dust-exposed subjects (n = 70) with WTC lung injury. Similarly, MDC clustered with GRO and MCP-1. WTC-PM(10-53) consistently induced more cytokine release than WTC-PM(2.5) at 100 µg/mL. Individual baseline expression correlated with WTC-PM-induced GM-CSF and MDC.WTC-PM(10-53) induced a stronger inflammatory response by human AM than WTC-PM(2.5). This large particle exposure may have contributed to the high incidence of lung injury in those exposed to particles at the WTC site. GM-CSF and MDC consistently cluster separately, suggesting a role for differential cytokine release in WTC-PM injury. Subject-specific response to WTC-PM may underlie individual susceptibility to lung injury after irritant dust exposure.
Published: 2012
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17. The Role of Glutathione Reductase in Influenza Infection

Author: Kyung Sook Hong, Kassandra Pagan, William Whalen, Rebecca Harris, Jianjun Yang, Heather Stout-Delgado, and Soo Jung Cho
Subjects: Male, Pulmonary and Respiratory Medicine, Mice, Inbred BALB C, Clinical Biochemistry, Lung Injury, Cell Biology, Glutathione, Antioxidants, Mice, Glutathione Reductase, Influenza A Virus, H1N1 Subtype, Orthomyxoviridae Infections, Influenza, Human, Animals, Humans, RNA, Female, Lung, Molecular Biology, Original Research
Abstract: Influenza infection induces lung epithelial cell injury via programmed cell death. Glutathione, a potent antioxidant, has been reported to be associated with influenza infection. We hypothesized that lung epithelial cell death during influenza infection is regulated by glutathione metabolism. Eight-week-old male and female BALB/c mice were infected with influenza (PR8: A/PR/8/34 [H1N1]) via intranasal instillation. Metabolomic analyses were performed on whole lung lysate after influenza infection. Foriin vitro/ianalysis, Beas-2B cells were infected with influenza. RNA was extracted, and QuantiTect Primer Assay was used to assess gene expression. Glutathione concentrations were assessed by colorimetric assay. Influenza infection resulted in increased inflammation and epithelial cell injury in our murine model, leading to increased morbidity and mortality. In both ouriin vivo/iandiin vitro/imodels, influenza infection was found to induce apoptosis and necroptosis. Influenza infection led to decreased glutathione metabolism and reduced glutathione reductase activity in lung epithelial cells. Genetic inhibition of glutathione reductase suppressed apoptosis and necroptosis of lung epithelial cells. Pharmacologic inhibition of glutathione reductase reduced airway inflammation, lung injury, and cell death in our murine influenza model. Our results demonstrate that glutathione reductase activity is suppressed during influenza. Glutathione reductase inhibition prevents epithelial cell death and morbidity in our murine influenza model. Our results suggest that glutathione reductase-dependent glutathione metabolism may play an important role in the host response to viral infection by regulating lung epithelial cell death.
Published: 2022

18. Crosstalk between necroptosis and the inflammasome

Author: Soo Jung Cho, Alexander Pronko, and Heather Stout-Delgado
Published: 2023

19. Contributors

Author: Antonio Abbate, Ivona Aksentijevich, Marcelo Pires Amaral, Magaiver Andrade-Silva, Diego Angosto-Bazarra, Luca Antonioli, Kübra Aral, Juan I. Aróstegui, Jillian Barlow, Laura Benvenuti, Nunzia Bernardini, Massimo Bertinaria, Monika Biasizzo, Karina Ramalho Bortoluci, Dave Boucher, Laura Migliari Branco, David Brough, Petr Broz, Clare E. Bryant, Mark Cahill, Matthew Campbell, Soo Jung Cho, Shelbi Christgen, Rebecca C. Coll, Isabelle Couillin, Brianna Cyr, Sarah Dalmon, Juan Pablo de Rivero Vaccari, Francesco Di Virgilio, Andrea Dorfleutner, Sarah L. Doyle, Vanessa D'Antongiovanni, Ariel E. Feldstein, Matteo Fornai, Carlos García-Palenciano, Simone Gastaldi, Matthias Geyer, François Ghiringhelli, Anna Lisa Giuliani, José Manuel González-Navajas, Iva Hafner-Bratkovič, Shaima'a Hamarsheh, Michael T. Heneka, Thomas Henry, Jun-ichi Hikima, Inga V. Hochheiser, Alexander Hogg, Alexander Hooftman, Christopher Hoyle, Yin Huang, Sarah Huot-Marchand, Laura Hurtado-Navarro, Sushmita Jha, Thirumala-Devi Kanneganti, Benedikt Kaufmann, Andrea D. Kim, Nataša Kopitar-Jerala, Jordana Kron, Silvia Lucena Lage, Beatriz Lozano-Ruiz, Elisabetta Marini, Billie Matchett, Adolfo G. Mauro, Eleonora Mezzaroma, Michael R. Milward, Ingrid Kazue Mizuno Watanabe, Natsuki Morimoto, Sandip Mukherjee, Mar Orzáez, Luke A.J. O'Neill, Pablo Pelegrín, Carolina Pellegrini, Anaïs Perrichet, Joanna Picó, Nicola Potere, Alexander Pronko, Kishore Aravind Ravichandran, Nicolas Riteau, Kim S. Robinson, Cédric Rébé, Fadi N. Salloum, Mónica Sancho, Andrew Sandstrom, Niels Olsen Saraiva Câmara, Florian I. Schmidt, Liang Shan, Eoin Silke, Paula M. Soriano-Teruel, Christian Stehlik, Heather Stout-Delgado, Arianne L. Theiss, Jenny P.-Y. Ting, Stefano Toldo, Elviche L. Tsakem, Rebecca E. Tweedell, Amalia Tzoumpa, K. Venuprasad, Rose Wellens, Robert Zeiser, Franklin L. Zhong, and Alessia Zotta
Published: 2023

20. Urine-based multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Author: Richa Batra, Rie Uni, Oleh M. Akchurin, Sergio Alvarez-Mulett, Luis G. Gómez-Escobar, Edwin Patino, Katherine L. Hoffman, Will Simmons, Kelsey Chetnik, Mustafa Buyukozkan, Elisa Benedetti, Karsten Suhre, Edward Schenck, Soo Jung Cho, Augustine M.K. Choi, Frank Schmidt, Mary E. Choi, and Jan Krumsiek
Subjects: Article
Abstract: Acute respiratory distress syndrome (ARDS), a life-threatening condition during critical illness, is a common complication of COVID-19. It can originate from various disease etiologies, including severe infections, major injury, or inhalation of irritants. ARDS poses substantial clinical challenges due to a lack of etiology-specific therapies, multisystem involvement, and heterogeneous, poor patient outcomes. A molecular comparison of ARDS groups holds the potential to reveal common and distinct mechanisms underlying ARDS pathogenesis. In this study, we performed a comparative analysis of urine-based metabolomics and proteomics profiles from COVID-19 ARDS patients (n = 42) and bacterial sepsis-induced ARDS patients (n = 17). The comparison of these ARDS etiologies identified 150 metabolites and 70 proteins that were differentially abundant between the two groups. Based on these findings, we interrogated the interplay of cell adhesion/extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis through a multi-omic network approach. Moreover, we identified a proteomic signature associated with mortality in COVID-19 ARDS patients, which contained several proteins that had previously been implicated in clinical manifestations frequently linked with ARDS pathogenesis. In summary, our results provide evidence for significant molecular differences in ARDS patients from different etiologies and a potential synergy of extracellular matrix molecules, inflammation, and mitochondrial dysfunction in ARDS pathogenesis. The proteomic mortality signature should be further investigated in future studies to develop prediction models for COVID-19 patient outcomes.
Published: 2022

21. Association of Surge Conditions with Mortality Among Critically Ill Patients with COVID-19

Author: Adam B. Keene, Andrew J. Admon, Samantha K. Brenner, Shruti Gupta, Deepa Lazarous, David E. Leaf, Hayley B. Gershengorn, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Shahzad Shaefi, Brian P. O’Gara, Megan L. Krajewski, Sean M. Baskin, Sidharth Shankar, Juan D. Valencia, Ameeka Pannu, Margaret M. Hayes, E. Wilson Grandin, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Shristi Upadhyay, Ishaan Vohra, Ajiboye Oyintayo, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, Aquino Williams, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Miguel A. Hernán, Rebecca Lisk, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Pattharawin Pattharanitima, Emily J. Gallagher, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, Samir C. Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddhartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Dheeraj Reddy Sirganagari, Pramod K. Guru, Kianoush Kashani, Shahrzad Tehranian, Yan Zhou, Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Michal L. Melamed, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Neelja Kumar, Michael Chang, Jyotsana Thakkar, Ritesh Raichoudhury, Akshay Athreya, Mohamed Farag, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Sobaata Chaudhry, Benjamin Wu, Frank Modersitzki, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner MB. Mohamed, Rupali S. Avasare, David Zonies, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Ariel L. Mueller, Roberta E. Redfern, Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, Laura Bickley, Chris Rowan, Farah Madhani-Lovely, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, Mark Liotta, Jared Radbel, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth S. Vatson, Shuchi Anand, Joseph E. Levitt, Pablo Garcia, Suzanne M. Boyle, Rui Song, Ali Arif, Jingjing Zhang, Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, Katharine Senter, Moh’d A. Sharshir, Vadym V. Rusnak, Muhammad Imran Ali, Terri Peters, Kathy Hughes, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Arash Rashidi, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Carl E. Schulze, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Alissa Kunczt, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Madona Elias, Yahya Ahmad, Rajany Dy, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Alessia Fornoni, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O' Hayer, Chelsea Meloche, Rafey Feroze, Kishan J. Padalia, Abbas Bitar, Jeff Leya, John P. Donnelly, Jennifer E. Flythe, Matthew J. Tugman, Emily H. Chang, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, Huiwen Chen, Csaba P. Kovesdy, Miklos Z. Molnar, Ambreen Azhar, S. Susan Hedayati, Mridula V. Nadamuni, Shani Shastri, Duwayne L. Willett, Samuel A.P. Short, Amanda D. Renaghan, Kyle B. Enfield, Pavan K. Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Nitender Goyal, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Ravi K. Kshirsagar, Aju Jose, Daniel E. Weiner, Marta Christov, Savneek Chugh, Jennifer Griffiths, Sanjeev Gupta, Aromma Kapoor, Perry Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: Adult, Cohort Studies, Male, Intensive Care Units, SARS-CoV-2, Critical Illness, COVID-19, Humans, Female, Hospital Mortality, Middle Aged, Critical Care and Intensive Care Medicine
Abstract: Objective To determine whether surge conditions were associated with increased mortality. Design Multicenter cohort study. Setting U.S. ICUs participating in STOP-COVID. Patients Consecutive adults with COVID-19 admitted to participating ICUs between March 4 and July 1, 2020. Interventions None Measurements and Main Results The main outcome was 28-day in-hospital mortality. To assess the association between admission to an ICU during a surge period and mortality, we used two different strategies: (1) an inverse probability weighted difference-in-differences model limited to appropriately matched surge and non-surge patients and (2) a meta-regression of 50 multivariable difference-in-differences models (each based on sets of randomly matched surge- and non-surge hospitals). In the first analysis, we considered a single surge period for the cohort (March 23 – May 6). In the second, each surge hospital had its own surge period (which was compared to the same time periods in matched non-surge hospitals). Our cohort consisted of 4342 ICU patients (average age 60.8 [sd 14.8], 63.5% men) in 53 U.S. hospitals. Of these, 13 hospitals encountered surge conditions. In analysis 1, the increase in mortality seen during surge was not statistically significant (odds ratio [95% CI]: 1.30 [0.47-3.58], p = .6). In analysis 2, surge was associated with an increased odds of death (odds ratio 1.39 [95% CI, 1.34-1.43], p Conclusions Admission to an ICU with COVID-19 in a hospital that is experiencing surge conditions may be associated with an increased odds of death. Given the high incidence of COVID-19, such increases would translate into substantial excess mortality.
Published: 2021

22. Kidney Recovery and Death in Critically Ill Patients With COVID-19-Associated Acute Kidney Injury Treated With Dialysis: The STOP-COVID Cohort Study

Author: Caroline M. Hsu, Shruti Gupta, Hocine Tighiouart, Nitender Goyal, Anthony J. Faugno, Asma Tariq, Ritesh Raichoudhury, Jill H. Sharma, Leah Meyer, Ravi K. Kshirsagar, Aju Jose, David E. Leaf, Daniel E. Weiner, Hsu Gupta, Goyal Faugno, Tariq Raichoudhury, Sharma Meyer, Kshirsagar Leaf, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Kenneth A. Bauer, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Shristi Upadhyay, Ishaan Vohra, Ajiboye Oyintayo, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, Aquino WilliamsSamantha K. Brenner, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Miguel A. Hernán, Amy M. Zhou, Ethan C. Kim, Rebecca Lisk, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Pattharawin Pattharanitima, Emily J. Gallagher, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, Samir C. Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddhartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Dheeraj Reddy Sirganagari, Pramod K. Guru, Kianoush Kashani, Shahrzad Tehranian, Yan Zhou, Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Michal L. Melamed, Tanya S. Johns. Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Jyotsana Thakkar, Neelja Kumar, Michael J. Ross, Michael Chang, Akshay Athreya, Mohamed Farag, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner M.B. Mohamed, Rupali S. Avasare, David Zonies, Hanny Al-Samkari, Rebecca Karp Leaf, Rachel Rosovsky, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Wei Wang, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Ariel L. Mueller, Roberta E. Redfern, Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, Laura Bickley, Chris Rowan, Farah Madhani-Lovely, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, Mark Liotta, Jared Radbel, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth S. Vatson, George Karp, Shuchi Anand, Joseph E. Levitt, Pablo Garcia, Suzanne M. Boyle, Rui Song, Jingjing Zhang, Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, Moh’d A. Sharshir, Vadym V. Rusnak, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Arash Rashidi, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Carl E. Schulze, Etienne Macedo, Harin RheeKa, null thleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Madona Elias, Yahya Ahmad, Rajany Dy, Alfredo Iardino, Elizabeth H. Au, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Hayley B. Gershengorn, Alessia Fornoni, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’Hayer, Chelsea Meloche, Rafey Feroze, Kishan J. Padalia, Jeff Leya, John P. Donnelly, Andrew J. Admon, Jennifer E. Flythe, Matthew J. Tugman, Emily H. Chang, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, Huiwen Chen, Csaba P. Kovesdy, Miklos Z. Molnar, Ambreen Azhar, S. Susan Hedayati, Mridula V. Nadamuni, Shani Shastri, Duwayne L. Willett, Samuel A.P. Short, Amanda D. Renaghan, Kyle B. Enfield, Pavan K. Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Marta Christov, Jennifer Griffiths, Sanjeev Gupta, Aromma Kapoor, Savneek Chugh, Perry Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: Adult, urogenital system, SARS-CoV-2, Critical Illness, Aftercare, COVID-19, Original Investigations, Acute Kidney Injury, urologic and male genital diseases, Kidney, Patient Discharge, Cohort Studies, critical care, Intensive Care Units, Nephrology, Renal Dialysis, Risk Factors, urine output, Humans, dialysis, chronic kidney disease, Retrospective Studies
Abstract: Rationale & Objective Acute kidney injury treated with kidney replacement therapy (AKI-KRT) occurs frequently in critically ill patients with COVID-19. We examined the clinical factors that determine kidney recovery in this population. Study Design Multicenter cohort study. Setting & Participants 4221 adults with COVID-19 not receiving kidney replacement therapy who were admitted to intensive care units at 68 US hospitals with COVID-19 from March 1 to June 22, 2020 (the “ICU cohort”). Among these, 876 developed AKI-KRT after admission to the ICU (the “AKI-KRT subcohort”). Exposure(s) The ICU cohort was analyzed using AKI severity as the exposure. For the AKI-KRT subcohort, exposures included demographics, comorbidities, initial mode of KRT, and markers of illness severity at the time of dialysis initiation. Outcome(s) The outcome for the ICU cohort was estimated glomerular filtration rate (GFR) at hospital discharge. A three-level outcome including death, kidney nonrecovery, and kidney recovery at discharge, was analyzed for the AKI-KRT subcohort. Analytical approach The ICU cohort was characterized using descriptive analyses. The AKI-KRT subcohort was characterized with both descriptive analyses and multinomial logistic regression to assess factors associated with kidney nonrecovery while accounting for death. Results Among a total of 4221 patients in the ICU cohort, 2361 (56%) developed AKI, including 876 (21%) who received KRT. More severe AKI was associated with higher mortality. Among survivors, more severe AKI was associated with an increased rate of kidney nonrecovery and lower kidney function at discharge. Among the 876 patients with AKI-KRT, 588 (67%) died, 95 (11%) had kidney nonrecovery, and 193 (22%) had kidney recovery by the time of discharge. The odds of kidney nonrecovery was greater for lower estimated GFR with odds ratios (ORs) of 2.09 (95% CI, 1.09-4.04), 4.27 (95% CI, 1.99-9.17), and 8.69 (95% CI, 3.07-24.55) for CKD GFR categories 3, 4, and 5, respectively, compared to estimated GFR > 60 mL/min/1.73 m2. Oliguria at the time of KRT initiation was also associated with nonrecovery (OR 2.10 [95% CI, 1.14-3.88] and 4.02 [95% CI, 1.72-9.39] for patients with 50-499 and, Critically ill patients with COVID-19 often develop acute kidney injury (AKI). This study of 4221 patients demonstrated that more severe AKI was associated with greater in-hospital mortality and poorer kidney function at hospital discharge. Among the 876 patients who required dialysis for AKI, almost two-thirds died. Among those who survived to discharge, about two-thirds recovered kidney function and were discharged without the need for dialysis. Lower baseline kidney function and reduced urine output were associated with non-recovery of kidney function. Identification of such predictors is important in assessing prognosis among these critically ill patients and has implications for clinical care of individuals critically ill with COVID-19.
Published: 2021

23. Integrative metabolomic and proteomic signatures define clinical outcomes in severe COVID-19

Author: Mustafa Buyukozkan, Sergio Alvarez-Mulett, Alexandra C. Racanelli, Frank Schmidt, Richa Batra, Katherine L. Hoffman, Hina Sarwath, Rudolf Engelke, Luis Gomez-Escobar, Will Simmons, Elisa Benedetti, Kelsey Chetnik, Guoan Zhang, Edward Schenck, Karsten Suhre, Justin J. Choi, Zhen Zhao, Sabrina Racine-Brzostek, He S. Yang, Mary E. Choi, Augustine M.K. Choi, Soo Jung Cho, and Jan Krumsiek
Subjects: ARDS, Multidisciplinary, Coronavirus disease 2019 (COVID-19), Proteomic Profiling, business.industry, Acute kidney injury, Disease, medicine.disease, Bioinformatics, medicine.disease_cause, Metabolomics, medicine, business, Asymptomatic carrier, Coronavirus
Abstract: The novel coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2 has ravaged global healthcare with previously unseen levels of morbidity and mortality. To date, methods to predict the clinical course, which ranges from the asymptomatic carrier to the critically ill patient in devastating multi-system organ failure, have yet to be identified. In this study, we performed large-scale integrative multi-omics analyses of serum obtained from COVID-19 patients with the goal of uncovering novel pathogenic complexities of this disease and identifying molecular signatures that predict clinical outcomes. We assembled a novel network of protein-metabolite interactions in COVID-19 patients through targeted metabolomic and proteomic profiling of serum samples in 330 COVID-19 patients compared to 97 non-COVID, hospitalized controls. Our network identified distinct protein-metabolite cross talk related to immune modulation, energy and nucleotide metabolism, vascular homeostasis, and collagen catabolism. Additionally, our data linked multiple proteins and metabolites to clinical indices associated with long-term mortality and morbidity, such as acute kidney injury. Finally, we developed a novel composite outcome measure for COVID-19 disease severity and created a clinical prediction model using a set of 33 metabolites. The model significantly improved the identification of key events of critical illness such as prolonged hospitalization, supplemental oxygen requirement, acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS), beyond those achieved using the more traditional risk factors of age, gender, and BMI.
Published: 2021

24. RIPK3 Activates MLKL-mediated Necroptosis and Inflammasome Signaling during Streptococcus Infection

Author: Soo Jung Cho, Heather W. Stout-Delgado, Jianjun Yang, Rebecca M. Harris, Charles S. Dela Cruz, Hua-Rong Huang, Santos Bermejo, Jin-Fu Xu, and Lokesh Sharma
Subjects: Male, Inflammasomes, Clinical Biochemistry, medicine.disease_cause, Mice, Mitochondrial calcium uptake, Original Research, Mice, Knockout, Inflammasome, Middle Aged, Mitochondria, Streptococcus pneumoniae, Receptor-Interacting Protein Serine-Threonine Kinases, Pneumococcal pneumonia, Necroptosis, Female, medicine.symptom, medicine.drug, Signal Transduction, Pulmonary and Respiratory Medicine, Inflammation, Microbiology, Necrosis, Macrophages, Alveolar, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, Molecular Biology, Aged, business.industry, Mitochondrial Permeability Transition Pore, Editorials, Cell Biology, Pneumonia, Pneumococcal, medicine.disease, respiratory tract diseases, Mice, Inbred C57BL, Pneumonia, Disease Models, Animal, Mitochondrial permeability transition pore, Gene Expression Regulation, Case-Control Studies, Calcium Channels, business, Reactive Oxygen Species, Protein Kinases, Proto-Oncogene Proteins c-akt
Abstract: Community-acquired pneumonia is the most common type of pneumonia and remains a leading cause of morbidity and mortality worldwide. Although many different pathogens can contribute to pneumonia, Streptococcus pneumoniae is one of the common bacterial pathogens that underlie community-acquired pneumonia. RIPK3 (receptor-interacting protein kinase 3) is widely recognized as a key modulator of inflammation and cell death. To elucidate a potential role of RIPK3 in pneumonia, we examined plasma from healthy control subjects and patients positive for streptococcal pneumonia. In human studies, RIPK3 protein concentrations were significantly elevated and were identified as a potential plasma marker of pneumococcal pneumonia. To expand these findings, we used an in vivo murine model of pneumococcal pneumonia to demonstrate that RIPK3 deficiency leads to reduced bacterial clearance, severe pathological damage, and high mortality. Our results illustrated that RIPK3 forms a complex with RIPK1, MLKL (mixed-lineage kinase domain-like protein), and MCU (mitochondrial calcium uniporter) to induce mitochondrial calcium uptake and mitochondrial reactive oxygen species(mROS) production during S. pneumoniae infection. In macrophages, RIPK3 initiated necroptosis via the mROS-mediated mitochondrial permeability transition pore opening and NLRP3 inflammasome activation via the mROS-AKT pathway to protect against S. pneumoniae. In conclusion, our study demonstrated a mechanism by which RIPK3-initiated necroptosis is essential for host defense against S. pneumoniae.
Published: 2021

25. Hospital-Level Variation in Death for Critically Ill Patients with COVID-19

Author: Matthew M. Churpek, Shruti Gupta, Alexandra B. Spicer, William F. Parker, John Fahrenbach, Samantha K. Brenner, David E. Leaf, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Shristi Upadhyay, Ishaan Vohra, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, Aquino Williams, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Miguel A. Hernán, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Pattharawin Pattharanitima, Emily J. Gallagher, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Elena Cervantes, Samir Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Dheeraj Reddy Sirganagari, Pramod K. Guru, Kianoush Kashani, Shahrzad Tehranian, Yan Zhou, Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Michal L. Melamed, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Neelja Kumar, Michael Chang, Jyotsana Thakkar, Ritesh Raichoudhury, Akshay Athreya, Mohamed Farag, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Sobaata Chaudhry, Benjamin Wu, Frank Modersitzki, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner M. B. Mohamed, Rupali S. Avasare, David Zonies, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Ariel L. Mueller, Roberta Redfern, Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, Laura Bickley, Chris Rowan, Farah Madhai-Lovely, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, Mark Liotta, Jared Radbel, Jag Sunderram, Sonika Puri, Jayanth S. Vatson, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Shuchi Anand, Joseph E. Levitt, Pablo Garcia, Suzanne M. Boyle, Rui Song, Ali Arif, Jingjing Zhang, Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, Katharine Senter, Moh’d A. Sharshir, Vadym V. Rusnak, Muhammad Imran Ali, Terri Peters, Kathy Hughes, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Arash Rashidi, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Santa Monica, Carl E. Schulze, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Alessia Fornoni, Hayley B. Gershengorn, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’Hayer, Chelsea Meloche, Rafey Feroze, Rayan Kaakati, Danny Perry, Abbas Bitar, Elizabeth Anderson, Kishan J. Padalia, Christopher Launius, John P. Donnelly, Andrew J. Admon, Jennifer E. Flythe, Matthew J. Tugman, Emily H. Chang, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, Huiwen Chen, Csaba P. Kovesdy, Miklos Z. Molnar, Ambreen Azhar, S. Susan Hedayati, Mridula V. Nadamuni, Shani Shastri, Duwayne L. Willett, Samuel A. P. Short, Amanda D. Renaghan, Kyle B. Enfield, Pavan K. Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Nitender Goyal, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Ravi K. Kshirsagar, Daniel E. Weiner, Marta Christov, Jennifer Griffiths, Sanjeev Gupta, Aromma Kapoor, Perry Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, genetic structures, Coronavirus disease 2019 (COVID-19), Critical Illness, Disease, Comorbidity, Critical Care and Intensive Care Medicine, medicine.disease_cause, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Risk Factors, medicine, Humans, 030212 general & internal medicine, Hospital Mortality, Coronavirus, Aged, Retrospective Studies, Critically ill, business.industry, SARS-CoV-2, Incidence, Editorials, COVID-19, Hospital level, Middle Aged, Prognosis, Intensive care unit, Health equity, United States, Survival Rate, Intensive Care Units, Variation (linguistics), 030228 respiratory system, Emergency medicine, Female, business, Algorithms, Follow-Up Studies
Abstract: Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear.Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability.In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models.A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%).There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Published: 2021

26. Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis

Author: Fernando J. Martinez, Heather W. Stout-Delgado, Charles S. Dela Cruz, William Whalen, Bethany B. Moore, Jan Krumsiek, Soo Jung Cho, Augustine M.K. Choi, Mustafa Buyukozkan, and Jong-Seok Moon
Subjects: Pulmonary and Respiratory Medicine, business.industry, Lipid metabolism, Disease, DNA, respiratory system, medicine.disease, Pathophysiology, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Idiopathic pulmonary fibrosis, chemistry.chemical_compound, Metabolomics, chemistry, Immunology, Etiology, Disease Progression, Medicine, Humans, business, Double stranded, Cell-Free Nucleic Acids
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear aetiology and poorly understood pathophysiology. Although plasma levels of circulating cell-free DNA (ccf-DNA) and metabolomic changes have been reported in IPF, the associations between ccf-DNA levels and metabolic derangements in lung fibrosis are unclear. Here, we demonstrate that ccf-double-stranded DNA (dsDNA) is increased in patients with IPF with rapid progression of disease compared with slow progressors and healthy controls and that ccf-dsDNA associates with amino acid metabolism, energy metabolism and lipid metabolism pathways in patients with IPF.
Published: 2021

27. Performance of crisis standards of care guidelines in a cohort of critically ill COVID-19 patients in the United States

Author: Huei Hsun Wen, Vishal Jaikaransingh, Ernie Yap, Matthew T. Scharf, Jiahua Li, Samir Gautam, Jeffery O. Boateng, John Guirguis, Timothy E. Albertson, Shuchi Anand, Kathleen D. Liu, Amar D. Bansal, Alessia Fornoni, Caroline M. Hsu, Simon Correa, Natalie C. Ernecoff, Chris Rowan, William Feldman, Rupali S. Avasare, Maureen Brogan, Etienne Macedo, Nourhan Chaaban, Sabrina Taldone, Ryan Mocerino, Nilam P. Patel, Christopher Meshberger, Muner Mb. Mohamed, Joy-Marie Hermes, Ritesh Raichoudhury, Jamuna Krishnan, Amy M. Zhou, Abbas Bitar, Danny Perry, Barbara A. Danek, Allon N. Friedman, Salim S. Hayek, Richard G. Wunderink, Duwayne L. Willett, Moh’d A. Sharshir, Luis G. Gomez-Escobar, Wei Wang, Nicholas S. Cairl, Lisa Shea, Miguel A. Hernán, Christa A. Schorr, Rubab F. Malik, Patricia F. Kao, John Wagner, Patrick O’ Hayer, Sonika Puri, Shreyak Sharma, Mariah Thaxton, Seble G. Kassaye, Sidharth Shankar, Paul A. Bergl, Hayley B. Gershengorn, Sanjeev Gupta, Ibrahim Mohamed, Sushrut S. Waikar, Dheeraj Reddy Sirganagari, Jill H. Sharma, Gohar Mosoyan, Kyle B. Enfield, Ian A. Strohbehn, Thuy-Duyen Nguyen, Suzanne M. Boyle, Brent Brown, Rebecca V. Levy, Vasantha K. Jotwani, Alexandre M. Shehata, Maria Plataki, Julia L. Jezmir, Valerie Allusson, Jennifer Griffiths, Chirag R. Parikh, Alfredo Iardino, Emily H. Chang, Sanjana Kapoor, Tanira Ferreira, Harin Rhee, Nicholas Sadovnikoff, Aquino Williams, Vivian S. Cruz, Jay L. Koyner, Kristen M. Hess, Leon Boudourakis, Shahzad Shaefi, Vasil Peev, Omer Kamal, Ugochukwu Ugwuowo, Aromma Kapoor, Anitha Vijayan, Jared Radbel, Husam Shadid, Vadym V. Rusnak, Pattharawin Pattharanitima, Aju Jose, Yohannes Adama Melaku, Jayanth S. Vatson, Tariq U. Azam, Yahya Ahmad, William Whalen, Meghan Lee, Shani Shastri, David De La Zerda, Goni Katz-Greenberg, Hanna Berlin, Todd A. Miano, Seth Goldberg, Jatan A. Shah, Frank Modersitzki, Jag Sunderram, Anna E. Hasty, Esha M. Kapania, Samantha K. Brenner, Pennelope K. Blakely, Elizabeth H. Au, Ronaldo C. Go, Keith M. Rose, Anand Srivastava, Kathleen F. Kopecky, Ilya Berim, Alexander Chaitoff, Danyell Hall, Jingjing Zhang, Michel Chonchol, Gabriel Naimy, Sejal B. Shah, Stephanie M. Toth-Manikowski, Christina Mariyam Joy, Deepa G. Lazarous, Matthew W. Semler, Mark Liotta, Mridula V. Nadamuni, Greg L. Schumaker, Patricia Walters, Joseph E. Levitt, Steven G. Coca, Rana Hejal, Stefi Lee, Pramod Guru, Noor ul aain Bhatti, Jennifer E. Flythe, Daniel L. Edmonston, Asma Tariq, John J. Byun, Jesus Rodriguez, Mrigank S. Gupta, Andrew Vissing, Michal L. Melamed, Howard Soh, Adam E. Green, Yorg Azzi, Ladan Golestaneh, Amee Patrawalla, Amber S. Podoll, Ryan C. Spiardi, Xiaoying Deng, Ishaan Vohra, Carl P. Walther, Michael Chang, John P. Donnelly, David M. Charytan, Anthony J. Faugno, Peter Hart, Ameeka Pannu, Sandeep P. Kishore, Roberta E. Redfern, Ambreen Azhar, Meghan E. Sise, Di Pan, Sang Hoon Woo, H. Bryant Nguyen, Pavan K. Bhatraju, Bradford Diephuis, Justin Arunthamakun, Kaltrina Sedaliu, Ajiboye Oyintayo, Aimee Milliken, Andrew J Admon, Elena Cervantes, Erik T. Newman, Heather Yang, Lili Chan, Nitender Goyal, Peter Cangialosi, Arash Rashidi, David Zonies, Juan D. Valencia, Rebecca Lisk, Zoe Post, Farah Madhani-Lovely, Benjamin M. Wu, Princy N. Kumar, Ethan C. Kim, Maheetha Bharadwaj, Chintan V. Shah, A. Bilal Malik, Siddartha Bajracharya, Gabriela Bambrick-Santoyo, Conor P. Crowley, Ellen L. Burnham, Kianoush Kashani, Ashley Macina, Diana Finkel, Rebecca M. Beutler, Sowminya Arikapudi, Ayesha Ahmed, Edward J. Schenck, Kishan Padalia, Aparna Saha, Alexander J. Hodakowski, Tanya S. Johns, Rayan Kaakati, James P. Lash, Bhavarth Shukla, Mary Mallappallil, Eboni G. Price-Haywood, Steven Menez, Samaya J. Anumudu, Christopher L. Mosher, Rajat Kapoor, Harkarandeep Singh, Amanda K. Leonberg-Yoo, Rui Song, Samah Abu Omar, Laura Latta, Siddharth Verma, Steven Y. Chang, Soo Jung Cho, Emily Leven, Denzel Zhu, Jing G. Wang, Katharine Senter, Bijal Mehta, Ariel Mueller, Peter A. McCullough, Alexander S. Leidner, Milagros Yunes, Akshay Athreya, Carlos Martinez, Muhammad Imran Ali, Matthew J. Tugman, Laura Bickley, Perry Wilson, Chanu Rhee, Ambarish M. Athavale, Shruti Gupta, Samuel A.P. Short, S. Susan Hedayati, Neelja Kumar, Abeer Abu-Saif, Jeffrey M. Paer, Sobaata Chaudhry, Louis T. Merriam, Jochen Reiser, Gabriel Contreras, Eric Judd, Isha Puri, Marta Christov, Afshin Ahoubim, Leslie F. Thomas, Tanima Arora, Eric Goralnick, Elizabeth Anderson, Csaba P. Kovesdy, Alanna L. Jacobs, Marie Anne Sosa, Ashita Tolwani, Ravi K. Kshirsagar, Jason Y. Adams, Tingting Li, Javier A. Neyra, Deena R. Altman, Anip Bansal, Katherine J. Kelly, Sunita Sharma, Jean-Sebastien Rachoin, Zoe A. Kibbelaar, Celia P. Corona-Villalobos, Juan Carlos Q. Velez, Tanveer Shaukat, Leah Meyer, Kalyan Prudhvi, Edy Y. Kim, Madona Elias, Brian T. Garibaldi, Miklos Z. Molnar, Megan L. Krajewski, Sabu John, Girish N. Nadkarni, Molly Fisher, Michael Pan, Zaza Cohen, Min J. Joo, Yumeng Wen, Kapil K. Pokharel, Kusum S. Mathews, Shristi Upadhyay, Charles R. Vasquez, Amanda DeMauro Renaghan, Sergio L. Alvarez-Mulett, Rafey Feroze, Jacqueline M. Kruser, Daniel E. Weiner, Anne Sutherland, Jie Ouyang, Mohamed Farag, Gregory P. Milligan, Meaghan S. Roche, Luis A. Matute-Trochez, Chelsea Meloche, Yan Zhou, Jyotsna Bhattacharya, Sonali Bose, and David E. Leaf
Subjects: Adult, Male, Medicine (General), medicine.medical_specialty, Exacerbation, Critical Care, Organ Dysfunction Scores, Critical Illness, Population, Comorbidity, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, R5-920, Intensive care, medicine, Humans, Hospital Mortality, Intensive care medicine, education, Pandemics, intensive care, Aged, Retrospective Studies, education.field_of_study, crisis standards of care, Receiver operating characteristic, business.industry, SARS-CoV-2, Crew Resource Management, Healthcare, COVID-19, Standard of Care, Middle Aged, medicine.disease, Triage, United States, medical ethics, Cohort, Practice Guidelines as Topic, SOFA score, Female, triage, business, Algorithms
Abstract: Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.
Published: 2021

28. Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States

Author: Jennifer E. Flythe, Magdalene M. Assimon, Matthew J. Tugman, Emily H. Chang, Shruti Gupta, Jatan Shah, Marie Anne Sosa, Amanda DeMauro Renaghan, Michal L. Melamed, F. Perry Wilson, Javier A. Neyra, Arash Rashidi, Suzanne M. Boyle, Shuchi Anand, Marta Christov, Leslie F. Thomas, Daniel Edmonston, David E. Leaf, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Shristi Upadhyay, Ishaan Vohra, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, Aquino Williams, Samantha K. Brenner, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Pattharawin Pattharanitima, Emily J. Gallagher, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, Samir C. Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddhartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Kianoush Kashani, Shahrzad Tehranian, Dheeraj Reddy Sirganagari, Pramod K. Guru, Yan Zhou, Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Neelja Kumar, Michael Chang, Jyotsana Thakkar, Ritesh Raichoudhury, Akshay Athreya, Mohamed Farag, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Sobaata Chaudhry, Benjamin Wu, Frank Modersitzki, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner M.B. Mohamed, Rupali S. Avasare, David Zonies, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Ariel L. Mueller, Roberta Redfern, Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, Laura Bickley, Chris Rowan, Farah Madhani-Lovely, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, Mark Liotta, Jared Radbel, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth S. Vatson, Joseph E. Levitt, Pablo Garcia, Rui Song, Jingjing Zhang, Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, Katharine Senter, Moh’d A. Sharshir, Vadym V. Rusnak, Muhammad Imran Ali, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Ronald Reagan, Steven Y. Chang, Rebecca M. Beutler, Santa Monica, Carl E. Schulze, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Alissa Kunczt, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Nourhan Chaaban, Rajany Dy, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Hayley B. Gershengorn, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’ Hayer, Chelsea Meloche, Rafey Feroze, Rayan Kaakati, Danny Perry, Abbas Bitar, Elizabeth Anderson, Kishan J. Padalia, John P. Donnelly, Andrew J. Admon, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, Huiwen Chen, Csaba P. Kovesdy, Miklos Z. Molnar, Ambreen Azhar, S. Susan Hedayati, Mridula V. Nadamuni, Shani Shastri, Duwayne L. Willett, Samuel A.P. Short, Amanda D. Renaghan, Kyle B. Enfield, Pavan K. Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Nitender Goyal, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Ravi K. Kshirsagar, Daniel E. Weiner, Aju Jose, Jennifer Griffiths, Sanjeev Gupta, Aromma Kapoor, Perry Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: medicine.medical_specialty, 030232 urology & nephrology, Renal function, Original Investigations, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Intensive care, medicine, critical illness, 030212 general & internal medicine, Survival analysis, Kidney, business.industry, SARS-CoV-2, Confounding, COVID-19, Retrospective cohort study, medicine.disease, medicine.anatomical_structure, Respiratory failure, Nephrology, end stage kidney disease, dialysis, business, chronic kidney disease, Kidney disease
Abstract: Rationale & Objective Underlying kidney disease is an emerging risk factor for more severe COVID-19 illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes. Study Design Retrospective cohort study Settings & Participants 4,264 critically ill COVID-19 patients (143 dialysis patients, 521 chronic kidney disease [CKD] patients, and 3,600 patients without CKD) admitted to ICUs at 68 hospitals in the United States. Predictor(s) Presence (versus absence) of pre-existing kidney disease Outcome(s) In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) Analytical Approach We used standardized differences to compare patient characteristics (values >0.10 indicate a meaningful difference between groups) and multivariable adjusted Fine and Gray survival models to examine outcome associations. Results Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median [quartile 1-quartile 3] days: 4 [2-9] for dialysis patients; 7 [3-10] for CKD patients; 7 [4-10] for patients without pre-existing kidney disease). More dialysis patients (25%) reported altered mental status than those with CKD (20%, standardized difference = 0.12) and no kidney disease (12%, standardized difference = 0.36). Half of dialysis and CKD patients died within 28-days of ICU admission versus 35% of patients without pre-existing kidney disease. Compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of 28-day in-hospital death (adjusted HR 1.41; 95% CI 1.09, 1.81), while patients with CKD had an intermediate risk (adjusted HR 1.25; 95% CI 1.08, 1.44). Limitations Potential residual confounding Conclusions Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies for this vulnerable population., Individuals with underlying kidney disease may be particularly vulnerable to severe COVID-19 illness, marked by multi-system organ failure, thrombosis, and a heightened inflammatory response. Among 4,264 critically ill adults with COVID-19 admitted to 68 intensive care units across the U.S., we found that both chronic kidney disease and dialysis patients had a ∼50% 28-day in-hospital mortality rate. Patients with underlying kidney disease had higher in-hospital mortality than patients without kidney disease, with patients on maintenance dialysis having the highest risk. As evidenced by differences in symptoms and clinical trajectories, patients with pre-existing kidney disease may have unique susceptibility to COVID-19-related complications which warrants additional study and special consideration in the pursuit and development of targeted therapies.
Published: 2021
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29. Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis

Author: Chia-Lang Hsu, Kiichi Nakahira, Shu Hisata, Augustine M.K. Choi, Yi Jung Chen, Soo Jung Cho, Divya Bhatia, Suzanne M. Cloonan, Mitsuru Imamura, Kuei-Pin Chung, Ziling Huang, Chong-Jen Yu, Mary E. Choi, and Li Chao Fan
Subjects: 0301 basic medicine, Science, MFN2, General Physics and Astronomy, Mice, Transgenic, 02 engineering and technology, Mitochondrion, Mitochondrial Dynamics, Article, General Biochemistry, Genetics and Molecular Biology, GTP Phosphohydrolases, Bleomycin, 03 medical and health sciences, Idiopathic pulmonary fibrosis, medicine, Animals, MFN1, lcsh:Science, Cells, Cultured, Phospholipids, Mice, Knockout, Respiratory tract diseases, Antibiotics, Antineoplastic, Multidisciplinary, Lung, biology, Lipid metabolism, General Chemistry, respiratory system, Lipid Metabolism, 021001 nanoscience & nanotechnology, medicine.disease, Lipids, Idiopathic Pulmonary Fibrosis, Mitochondria, 3. Good health, Cell biology, respiratory tract diseases, Fatty acid synthase, Cholesterol, 030104 developmental biology, medicine.anatomical_structure, mitochondrial fusion, Alveolar Epithelial Cells, biology.protein, lcsh:Q, 0210 nano-technology
Abstract: Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung., Mitochondria of alveolar type 2 epithelial cells (AEC2) in the lung have been suggested to play a role in the development of idiopathic pulmonary fibrosis (IPF). Here the authors show that loss of mitofusin1 and mitofusin2 in murine AEC2 cells leads to the development of lung fibrosis through the regulation of surfactant lipids.
Published: 2019

30. Mitochondrial Dysfunction in Aged Macrophages and Lung during Primary Streptococcus pneumoniae Infection is Improved with Pirfenidone

Author: Kristen T. Schiffer, Hua-Rong Huang, Rebecca M. Harris, Maria Plataki, Heather W. Stout-Delgado, Soo Jung Cho, and Ha Seon Yun
Subjects: Male, 0301 basic medicine, Pyridones, Cell Respiration, Population, lcsh:Medicine, Mitochondrion, medicine.disease_cause, Article, Antioxidants, Pneumococcal Infections, 03 medical and health sciences, Adenosine Triphosphate, 0302 clinical medicine, Superoxides, Streptococcus pneumoniae, medicine, Animals, education, lcsh:Science, Lung, Cellular Senescence, Membrane Potential, Mitochondrial, Mice, Inbred BALB C, education.field_of_study, Multidisciplinary, Innate immune system, business.industry, Macrophages, lcsh:R, Bacterial pneumonia, Pirfenidone, medicine.disease, Mitochondria, 3. Good health, Oxidative Stress, Pneumococcal infections, 030104 developmental biology, Gene Expression Regulation, Immunology, Female, lcsh:Q, business, 030217 neurology & neurosurgery, Oxidative stress, medicine.drug
Abstract: Pneumococcal infections remain a leading cause of death in older adults, with the most serious cases occurring in persons ≥65 years of age. There is an urgent need to investigate molecular pathways underlying these impairments and devise new therapeutics to modulate innate immunity. The goal of our current study is to understand the impact of chronological aging on mitochondrial function in response to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using chronologically aged murine models, our findings demonstrate that decreased ATP production is associated with dysregulated mitochondrial complex expression, enhanced oxidative stress, diminished antioxidant responses, and decreased numbers of healthy mitochondria in aged adult macrophages and lung in response to S. pneumoniae. Pre-treatment of aged macrophages with pirfenidone, an anti-fibrotic drug with antioxidant and anti-inflammatory properties, improved mitochondrial function and decreased cellular oxidative stress responses. In vivo administration of pirfenidone decreased superoxide formation, increased healthy mitochondria number, improved ATP production, and decreased inflammatory cell recruitment and pulmonary oedema in aged mouse lung during infection. Taken together, our data shed light on the susceptibility of older persons to S. pneumoniae and provide a possible therapeutic to improve mitochondrial responses in this population.
Published: 2019

31. Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

Author: Hanny Al-Samkari, Shruti Gupta, Rebecca Karp Leaf, Wei Wang, Rachel P. Rosovsky, Samantha K. Brenner, Salim S. Hayek, Hanna Berlin, Rajat Kapoor, Shahzad Shaefi, Michal L. Melamed, Anne Sutherland, Jared Radbel, Adam Green, Brian T. Garibaldi, Anand Srivastava, Amanda Leonberg-Yoo, Alexandre M. Shehata, Jennifer E. Flythe, Arash Rashidi, Nitender Goyal, Lili Chan, Kusum S. Mathews, S. Susan Hedayati, Rajany Dy, Stephanie M. Toth-Manikowski, Jingjing Zhang, Mary Mallappallil, Roberta E. Redfern, Amar D. Bansal, Samuel A.P. Short, Mark G. Vangel, Andrew J. Admon, Matthew W. Semler, Kenneth A. Bauer, Miguel A. Hernán, David E. Leaf, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Shristi Upadhyay, Ishaan Vohra, Ajiboye Oyintayo, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, Aquino Williams, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Amy M. Zhou, Ethan C. Kim, Rebecca Lisk, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Pattharawin Pattharanitima, Emily J. Gallagher, Allon N. Friedman, John Guirguis, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, Samir C. Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddhartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Dheeraj Reddy Sirganagari, Pramod K. Guru, Yan Zhou, Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Jyotsana Thakkar, Neelja Kumar, Michael J. Ross, Michael Chang, Ritesh Raichoudhury, Akshay Athreya, Mohamed Farag, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner M.B. Mohamed, Rupali S. Avasare, David Zonies, Rachel Rosovsky, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Ariel L. Mueller, Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, Laura Bickley, Chris Rowan, Farah Madhani-Lovely, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, Mark Liotta, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth S. Vatson, George Karp, Shuchi Anand, Joseph E. Levitt, Pablo Garcia, Suzanne M. Boyle, Rui Song, Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, Moh'd A. Sharshir, Vadym V. Rusnak, Muhammad Imran Ali, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Carl E. Schulze, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Chintan V. Shah, Vishal Jaikaransingh, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Madona Elias, Yahya Ahmad, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Hayley B. Gershengorn, Alessia Fornoni, Pennelope Blakely, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’Hayer, Chelsea Meloche, Rafey Feroze, Kishan J. Padalia, Jeff Leya, John P. Donnelly, Matthew J. Tugman, Emily H. Chang, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, Huiwen Chen, Csaba P. Kovesdy, Miklos Z. Molnar, Ambreen Azhar, Mridula V. Nadamuni, Shani Shastri, Duwayne L. Willett, Amanda D. Renaghan, Kyle B. Enfield, Pavan K. Bhatraju, A. Bilal Malik, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Ravi K. Kshirsagar, Daniel E. Weiner, Marta Christov, Jennifer Griffiths, Sanjeev Gupta, Aromma Kapoor, Savneek Chugh, Perry Wilson, Tanima Arora, and Ugochukwu Ugwuowo
Subjects: Male, medicine.medical_specialty, Critical Illness, Hemorrhage, 01 natural sciences, law.invention, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, law, Internal Medicine, medicine, Humans, 030212 general & internal medicine, 0101 mathematics, Survival rate, Original Research, Aged, Proportional hazards model, business.industry, SARS-CoV-2, Incidence (epidemiology), 010102 general mathematics, Hazard ratio, Anticoagulants, COVID-19, General Medicine, Venous Thromboembolism, Blood Coagulation Disorders, Middle Aged, Intensive care unit, United States, Survival Rate, Intensive Care Units, Emergency medicine, Observational study, Female, business, Cohort study
Abstract: Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival. Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. Primary Funding Source: None.
Published: 2021

32. Cytokine Signatures of End Organ Injury in COVID-19

Author: Sabrina E Racine-Brzostek, Katherine Hoffman, Soo Jung Cho, Mary E. Choi, Edward J. Schenck, Steven P. Salvatore, Luis Gomez-Escobar, Justin J Choi, Sergio Alvarez-Mulett, Heather W. Stout-Delgado, Augustine M.K. Choi, Alain C. Borczuk, He S. Yang, Zhen Zhao, and Manuel D. Galvan
Subjects: Male, 0301 basic medicine, ARDS, Chemokine, medicine.medical_treatment, Science, Article, Proinflammatory cytokine, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Humans, Medicine, 030212 general & internal medicine, Diffuse alveolar damage, Lung, Aged, Respiratory Distress Syndrome, Multidisciplinary, biology, business.industry, Acute kidney injury, COVID-19, Translational research, Acute Kidney Injury, Middle Aged, medicine.disease, Respiration, Artificial, Hospitals, Treatment Outcome, 030104 developmental biology, Cytokine, Case-Control Studies, Immunology, biology.protein, Infectious diseases, Cytokines, Female, New York City, Cytokine Release Syndrome, business
Abstract: Increasing evidence has shown that Coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunologic response. We aimed to assess the differences in inflammatory cytokines in COVID-19 patients compared to contemporaneously hospitalized controls and then analyze the relationship between these cytokines and the development of Acute Respiratory Distress Syndrome (ARDS), Acute Kidney Injury (AKI) and mortality. In this cohort study of hospitalized patients, done between March third, 2020 and April first, 2020 at a quaternary referral center in New York City we included adult hospitalized patients with COVID-19 and negative controls. Serum specimens were obtained on the first, second, and third hospital day and cytokines were measured by Luminex. Autopsies of nine cohort patients were examined. We identified 90 COVID-19 patients and 51 controls. Analysis of 48 inflammatory cytokines revealed upregulation of macrophage induced chemokines, T-cell related interleukines and stromal cell producing cytokines in COVID-19 patients compared to the controls. Moreover, distinctive cytokine signatures predicted the development of ARDS, AKI and mortality in COVID-19 patients. Specifically, macrophage-associated cytokines predicted ARDS , T cell immunity related cytokines predicted AKI and mortality was was associated with cytokines of activated immune pathways, of which IL-13 was universally correlated with ARDS, AKI and mortality. Histopathological examination of the autopsies showed diffuse alveolar damage with significant mononuclear inflammatory cell infiltration. Additionally, the kidneys demonstrated glomerular sclerosis, tubulointerstitial lymphocyte infiltration and cortical and medullary atrophy. These patterns of cytokine expression offer insight into the pathogenesis of COVID-19 disease, its severity, and subsequent lung and kidney injury suggesting more targeted treatment strategies.
Published: 2020

33. Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis.

Author: Whalen, William, Buyukozkan, Mustafa, Moore, Bethany, Jong-Seok Moon, Dela Cruz, Charles S., Martinez, Fernando J., Choi, Augustine M. K., Krumsiek, Jan, Stout-Delgado, Heather, Soo Jung Cho, Moon, Jong-Seok, and Cho, Soo Jung
Subjects: IDIOPATHIC pulmonary fibrosis, CIRCULATING tumor DNA, NLRP3 protein, MEDICAL sciences, ESSENTIAL amino acids, AMINO acid metabolism, RANK correlation (Statistics)
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear aetiology and poorly understood pathophysiology. Although plasma levels of circulating cell-free DNA (ccf-DNA) and metabolomic changes have been reported in IPF, the associations between ccf-DNA levels and metabolic derangements in lung fibrosis are unclear. Here, we demonstrate that ccf-double-stranded DNA (dsDNA) is increased in patients with IPF with rapid progression of disease compared with slow progressors and healthy controls and that ccf-dsDNA associates with amino acid metabolism, energy metabolism and lipid metabolism pathways in patients with IPF. [ABSTRACT FROM AUTHOR]
Published: 2022
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34. Essential Role of IDO1 in Metabolic Programming of Innate Immune Responses in Aged Lung During Influenza

Author: Stefi Lee, Rebecca Harris, Heather W. Stout-Delgado, Ermias Jirru, and Soo Jung Cho
Subjects: Innate immune system, Lung, medicine.anatomical_structure, business.industry, Immunology, Medicine, business
Published: 2020

35. Heightened ER Stress in Aged Lung Contributes to Dysregulated NLRP3 Inflammasome Activation During Influenza

Author: Soo Jung Cho, H. Stout-Delgado, R. Harris, and Jianjun Yang
Subjects: Lung, medicine.anatomical_structure, business.industry, Cancer research, Unfolded protein response, Medicine, NLRP3 inflammasome activation, business
Published: 2020

36. Enhanced dsDNA Release in Sting Deficient Lung Contributes to Increased ROS and cGAMP Mediated Inflammasome Priming and Activation

Author: Jianjun Yang, Ermias Jirru, Rebecca Harris, Soo Jung Cho, Heather W. Stout-Delgado, and Stefi Lee
Subjects: Sting, Lung, medicine.anatomical_structure, Chemistry, Immunology, medicine, Priming (immunology), Inflammasome, medicine.drug
Published: 2020

37. Aging and Lung Disease

Author: Heather W. Stout-Delgado and Soo Jung Cho
Subjects: 0301 basic medicine, Lung Diseases, ARDS, Aging, Physiology, Population, Inflammation, Disease, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, education, Lung, Cellular Senescence, Aged, education.field_of_study, COPD, business.industry, Middle Aged, medicine.disease, Pneumonia, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Immunology, medicine.symptom, business
Abstract: People worldwide are living longer, and it is estimated that by 2050, the proportion of the world's population over 60 years of age will nearly double. Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. As the aging population rapidly grows, it is essential to examine how alterations in cellular function and cell-to-cell interactions of pulmonary resident cells and systemic immune cells contribute to a higher risk of increased susceptibility to infection and development of chronic diseases, such as chronic obstructive pulmonary disease and interstitial pulmonary fibrosis. This review provides an overview of physiological, structural, and cellular changes in the aging lung and immune system that facilitate the development and progression of disease.
Published: 2019

38. NLRP3 inflammasome activation in aged macrophages is diminished during Streptococcus pneumoniae infection

Author: Soo Jung Cho, Heather W. Stout-Delgado, Augustine M.K. Choi, and Kristen T. Rooney
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Physiology, Inflammasome, Cell Biology, Biology, medicine.disease_cause, medicine.disease, 03 medical and health sciences, Pneumonia, Pneumococcal infections, 030104 developmental biology, 0302 clinical medicine, Older patients, Physiology (medical), Immunology, Streptococcus pneumoniae, medicine, Macrophage, NLRP3 inflammasome activation, Research Article, 030215 immunology, medicine.drug, Cause of death
Abstract: Pneumococcal infections are the eigth leading cause of death in the United States, and it is estimated that older patients (≥65 yr of age) account for the most serious cases. The goal of our current study is to understand the impact of biological aging on innate immune responses to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. With the use of in vitro and in vivo aged murine models, our findings demonstrate that age-enhanced unfolded protein responses (UPRs) contribute to diminished inflammasome assembly and activation during S. pneumoniae infection. Pretreatment of aged mice with endoplasmic reticulum chaperone and the stress-reducing agent tauroursodeoxycholic acid (TUDCA) decreased mortality in aged hosts that was associated with increased NLRP3 inflammasome activation, improved pathogen clearance, and decreased pneumonitis during infection. Taken together, our data provide new evidence as to why older persons are more susceptible to S. pneumoniae and provide a possible therapeutic target to decrease morbidity and mortality in this population.
Published: 2018

39. GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation

Author: Kyung Sook Hong, Ha Seon Yun, Heather W. Stout-Delgado, Jong Seok Moon, Kiichi Nikahira, Soo Jung Cho, Augustine M.K. Choi, Rebecca Harris, and Hua-Rong Huang
Subjects: Pulmonary and Respiratory Medicine, Exacerbation, Inflammasomes, Bleomycin, medicine.disease_cause, Interstitial Lung Disease, Pneumococcal Infections, Microbiology, Pathogenesis, 03 medical and health sciences, chemistry.chemical_compound, AIM2, Idiopathic pulmonary fibrosis, Gene Knockout Techniques, Mice, 0302 clinical medicine, Fibrosis, Streptococcus pneumoniae, medicine, pneumonia, Animals, Humans, Lung, 030304 developmental biology, 0303 health sciences, Glucose Transporter Type 1, business.industry, Microbiota, Inflammasome, respiratory system, interstitial fibrosis, medicine.disease, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, 3. Good health, carbohydrates (lipids), Disease Models, Animal, 030228 respiratory system, chemistry, Disease Progression, business, Glycolysis, medicine.drug
Abstract: BackgroundIdiopathic pulmonary fibrosis (IPF) is a rapidly progressive, fatal lung disease that affects older adults. One of the detrimental natural histories of IPF is acute exacerbation of IPF (AE-IPF), of which bacterial infection is reported to play an important role. However, the mechanism by which bacterial infection modulates the fibrotic response remains unclear.ObjectivesAltered glucose metabolism has been implicated in the pathogenesis of fibrotic lung diseases. We have previously demonstrated that glucose transporter 1 (GLUT1)-dependent glycolysis regulates fibrogenesis in a murine fibrosis model. To expand on these findings, we hypothesised that GLUT1-dependent glycolysis regulates acute exacerbation of lung fibrogenesis during bacterial infection via AIM2 inflammasome activation.ResultsIn our current study, using a murine model of Streptococcus pneumoniae (S. pneumoniae) infection, we investigated the potential role of GLUT1 on mediating fibrotic responses to an acute exacerbation during bleomycin-induced fibrosis. The results of our current study illustrate that GLUT1 deficiency ameliorates S. pneumoniae-mediated exacerbation of lung fibrosis (wild type (WT)/phosphate buffered saline (PBS), n=3; WT/S. pneumoniae, n=3; WT/Bleomycin, n=5 ; WT/Bleomycin+S. pneumoniae, n=7; LysM-Cre-Glut1fl/f/PBS, n=3; LysM-Cre-Glut1fl/fl/S. pneumoniae, n=3; LysM-Cre-Glut1fl/fl/Bleomycin, n=6; LysM-Cre-Glut1fl/fl/Bleomycin+S. pneumoniae, n=9, p=0.041). Further, the AIM2 inflammasome, a multiprotein complex essential for sensing cytosolic bacterial DNA as a danger signal, is an important regulator of this GLUT1-mediated fibrosis and genetic deficiency of AIM2 reduced bleomycin-induced fibrosis after S. pneumoniae infection (WT/PBS, n=6; WT/Bleomycin+S. pneumoniae, n=15; Aim2−/−/PBS, n=6, Aim2−/−/Bleomycin+S. pneumoniae, n=11, p=0.034). GLUT1 deficiency reduced expression and function of the AIM2 inflammasome, and AIM2-deficient mice showed substantial reduction of lung fibrosis after S. pneumoniae infection.ConclusionOur results demonstrate that GLUT1-dependent glycolysis promotes exacerbation of lung fibrogenesis during S. pneumoniae infection via AIM2 inflammasome activation.
Published: 2019

40. RIPK3 Activates MLKL-Driven Necroptosis and NLRP3 Inflammasome in Macrophages to Protect Against Streptococcus Pneumoniae

Author: Ha Seon Yun, H.W. Stout-Delgado, Augustine M.K. Choi, Soo Jung Cho, Hua-Rong Huang, J.-F. Xu, and R. Harris
Subjects: Necroptosis, Streptococcus pneumoniae, medicine, Inflammasome, Biology, medicine.disease_cause, medicine.drug, Microbiology
Published: 2019

41. Transforming Growth Factor Beta Regulates Epithelial Cell Death During Influenza Infection

Author: Kyung Sook Hong, R. Harris, Augustine M.K. Choi, H. Stout-Delgado, Soo Jung Cho, and Ha Seon Yun
Subjects: medicine.anatomical_structure, medicine, biology.protein, Transforming growth factor beta, Biology, Epithelium, Cell biology
Published: 2019

42. Pirfenidone Treatment Improves Mitochondrial Dysfunction in Aged Macrophages and Lung During Primary Streptococcus Pneumoniae Infection

Author: Heather W. Stout-Delgado, M. Plataki, K. Schiffer, Soo Jung Cho, and Rebecca M. Harris
Subjects: Lung, medicine.anatomical_structure, business.industry, Immunology, Streptococcus pneumoniae, Medicine, Pirfenidone, business, medicine.disease_cause, medicine.drug
Published: 2019

43. Laminin α1 is a genetic modifier of TGF-β1–stimulated pulmonary fibrosis

Author: Gary Peltz, Ivan O. Rosas, Chang-Min Lee, Ming Zheng, Won-Kyung Cho, Jin Wook Park, Jack A. Elias, Soo Jung Cho, Chun Geun Lee, Jae Hyun Lee, and Augustine M.K. Choi
Subjects: 0301 basic medicine, Mice, Inbred Strains, Smad2 Protein, Lung injury, Biology, Transforming Growth Factor beta1, Extracellular matrix, Mice, 03 medical and health sciences, Idiopathic pulmonary fibrosis, Fibrosis, Laminin, Pulmonary fibrosis, Genetic model, medicine, Animals, Humans, Lung, Cell Proliferation, Extracellular Matrix Proteins, Gene Expression Profiling, Lung Injury, General Medicine, Macrophage Activation, respiratory system, medicine.disease, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Mice, Inbred C57BL, 030104 developmental biology, Gene Expression Regulation, Cancer research, biology.protein, Proto-Oncogene Proteins c-akt, Myofibroblast, Research Article, Signal Transduction
Abstract: The pathogenetic mechanisms underlying the pathologic fibrosis in diseases such as idiopathic pulmonary fibrosis (IPF) are poorly understood. To identify genetic factors affecting susceptibility to IPF, we analyzed a murine genetic model of IPF in which a profibrotic cytokine (TGF-β1) was expressed in the lungs of 10 different inbred mouse strains. Surprisingly, the extent of TGF-β1-induced lung fibrosis was highly strain dependent. Haplotype-based computational genetic analysis and gene expression profiling of lung tissue obtained from fibrosis-susceptible and -resistant strains identified laminin α1 (Lama1) as a genetic modifier for susceptibility to IPF. Subsequent studies demonstrated that Lama1 plays an important role in multiple processes that affect the pulmonary response to lung injury and susceptibility to fibrosis, which include: macrophage activation, fibroblast proliferation, myofibroblast transformation, and the production of extracellular matrix. Also, Lama1 mRNA expression was significantly increased in lung tissue obtained from IPF patients. These studies identify Lama1 as the genetic modifier of TGF-β1 effector responses that significantly affects the development of pulmonary fibrosis.
Published: 2018

44. RIPK3 Activates MLKL-mediated Necroptosis and Inflammasome Signaling during Streptococcus Infection.

Author: Hua-Rong Huang, Soo Jung Cho, Harris, Rebecca M., Jianjun Yang, Bermejo, Santos, Sharma, Lokesh, Dela Cruz, Charles S., Jin-Fu Xu, and Stout-Delgado, Heather W.
Subjects: PNEUMONIA, STREPTOCOCCUS pneumoniae, RECEPTOR-interacting proteins, MITOCHONDRIA, COMMUNITY-acquired infections, CELL death
Abstract: Community-acquired pneumonia is the most common type of pneumonia and remains a leading cause of morbidity and mortality worldwide. Although many different pathogens can contribute to pneumonia, Streptococcus pneumoniae is one of the common bacterial pathogens that underlie community-acquired pneumonia. RIPK3 (receptor-interacting protein kinase 3) is widely recognized as a key modulator of inflammation and cell death. To elucidate a potential role of RIPK3 in pneumonia, we examined plasma from healthy control subjects and patients positive for streptococcal pneumonia. In human studies, RIPK3 protein concentrations were significantly elevated and were identified as a potential plasma marker of pneumococcal pneumonia. To expand these findings, we used an in vivo murine model of pneumococcal pneumonia to demonstrate that RIPK3 deficiency leads to reduced bacterial clearance, severe pathological damage, and high mortality. Our results illustrated that RIPK3 forms a complex with RIPK1, MLKL (mixed-lineage kinase domain-like protein), and MCU (mitochondrial calcium uniporter) to induce mitochondrial calcium uptake and mitochondrial reactive oxygen species(mROS) production during S. pneumoniae infection. In macrophages, RIPK3 initiated necroptosis via the mROS-mediated mitochondrial permeability transition pore opening and NLRP3 inflammasome activation via the mROS--AKT pathway to protect against S. pneumoniae. In conclusion, our study demonstrated amechanism by which RIPK3-initiated necroptosis is essential for host defense against S. pneumoniae. [ABSTRACT FROM AUTHOR]
Published: 2021
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45. Association of hemoglobin variability with the risk of cardiovascular disease: a nationally representative retrospective cohort study from South Korea

Author: Won Jung Lee, Seulggie Choi, Sang Min Park, Gyeongsil Lee, Jooyoung Chang, Yun Hwan Oh, Joung Sik Son, Kyae Hyung Kim, and Soo Jung Choi
Subjects: Medicine, Science
Abstract: Abstract Hemoglobin variability is known to increase cardiovascular mortality in chronic kidney disease, but the association of hemoglobin variability with the risk of cardiovascular disease (CVD) in the general population is yet unclear. This retrospective cohort study based on ‘the South Korean National Health Insurance Service database’ consisted of 198,347 adults who went through all three health examinations. Hemoglobin variability is defined as the average successive variability of three separate hemoglobin values from each health screening period. Participants were followed up for 6 years to determine the risk of coronary heart disease and stroke. We used multivariate Cox proportional hazards regression to examine the adjusted hazard ratios for CVD according to hemoglobin variability. Per 1 unit increase of hemoglobin variability, the risk for CVD (aHR 1.06, 95% CI 1.02–1.09) and stroke (aHR 1.08, 95% CI 1.03–1.13) increased significantly. The risk-increasing trend was preserved in the low-to-moderate risk group of CVDs (aHR 1.07, 95% CI 1.02–1.11). This result suggests that subjects with high hemoglobin variability who would otherwise be categorized as having low-to-moderate CVD risk may have higher risk of CVD than those with low hemoglobin variability.
Published: 2023
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46. Changes in Carotenoid Contents of Colored Pumpkin (Cucurbita spp.) Germplasms

Author: Jae-Hyeong Shin, Jung-Bong Kim, Soo-Jung Cho, Na-Young Ro, Min-Ki Lee, Sang Gyu Kim, Soo-Yeon Cho, Ho-Cheol Ko, Heon-Woong Kim, and Hyung-Jin Baek
Subjects: chemistry.chemical_classification, Lutein, chemistry.chemical_compound, Horticulture, chemistry, Colored, biology, Botany, General Medicine, Cucurbita, biology.organism_classification, Carotenoid
Published: 2015

47. Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung

Author: Stefi Lee, Heather W. Stout-Delgado, Rebecca Harris, Soo Jung Cho, Ermias Jirru, and Jianjun Yang
Subjects: 0301 basic medicine, medicine.medical_treatment, Secondary infection, Immunology, viral immune imprinting, lcsh:Medicine, medicine.disease_cause, Article, Virus, 03 medical and health sciences, 0302 clinical medicine, Immune system, Drug Discovery, Streptococcus pneumoniae, medicine, Pharmacology (medical), 030212 general & internal medicine, Pharmacology, Lung, vaccine effectiveness, business.industry, lcsh:R, aging, Vaccination, 030104 developmental biology, Infectious Diseases, Cytokine, medicine.anatomical_structure, Pneumococcal vaccine, influenza, business
Abstract: Changes in innate and adaptive immune responses caused by viral imprinting can have a significant direct or indirect influence on secondary infections and vaccine responses. The purpose of our current study was to investigate the role of immune imprinting by influenza on pneumococcal vaccine effectiveness during Streptococcus pneumoniae infection in the aged murine lung. Aged adult (18 months) mice were vaccinated with the pneumococcal polyvalent vaccine Pneumovax (5 mg/mouse). Fourteen days post vaccination, mice were instilled with PBS or influenza A/PR8/34 virus (3.5 &times, 102 PFU). Control and influenza-infected mice were instilled with PBS or S. pneumoniae (1 &times, 103 CFU, ATCC 6303) on day 7 of infection and antibacterial immune responses were assessed in the lung. Our results illustrate that, in response to a primary influenza infection, there was diminished bacterial clearance and heightened production of pro-inflammatory cytokines, such as IL6 and IL1&beta, Vaccination with Pneumovax decreased pro-inflammatory cytokine production by modulating NFҡB expression, however, these responses were significantly diminished after influenza infection. Taken together, the data in our current study illustrate that immune imprinting by influenza diminishes pneumococcal vaccine efficacy and, thereby, may contribute to increased susceptibility of older persons to a secondary infection with S. pneumoniae.
Published: 2020

48. Essential Role of Indoleamine 2, 3‐dioxygenase 1 ( IDO1 ) in Metabolic Programming of Innate Immune Responses in Aged Lung during Influenza

Author: Heather W. Stout-Delgado, Jianjun Yang, Soo Jung Cho, Rebecca Harris, and Kyung Sook Hong
Subjects: Lung, medicine.anatomical_structure, Innate immune system, Immunology, Genetics, medicine, Biology, Indoleamine 2,3-dioxygenase, Molecular Biology, Biochemistry, Biotechnology
Published: 2020

49. DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis

Author: Heather W. Stout-Delgado, Mihye Lee, Jong-Seok Moon, and Soo Jung Cho
Subjects: Ribonuclease III, aim2 inflammasome, drosha, Inflammasomes, Inflammation, Review, Models, Biological, Catalysis, lcsh:Chemistry, Inorganic Chemistry, Pathogenesis, Idiopathic pulmonary fibrosis, AIM2, ipf, microRNA, medicine, Animals, Humans, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Drosha, biology, Chemistry, Organic Chemistry, Inflammasome, General Medicine, respiratory system, medicine.disease, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Computer Science Applications, DNA-Binding Proteins, MicroRNAs, lcsh:Biology (General), lcsh:QD1-999, Cancer research, biology.protein, medicine.symptom, mirna, medicine.drug
Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Chronic lung inflammation is linked to the pathogenesis of IPF. DROSHA, a class 2 ribonuclease III enzyme, has an important role in the biogenesis of microRNA (miRNA). The function of miRNAs has been identified in the regulation of the target gene or protein related to inflammatory responses via degradation of mRNA or inhibition of translation. The absent-in-melanoma-2 (AIM2) inflammasome is critical for inflammatory responses against cytosolic double stranded DNA (dsDNA) from pathogen-associated molecular patterns (PAMPs) and self-DNA from danger-associated molecular patterns (DAMPs). The AIM2 inflammasome senses double strand DNA (dsDNA) and interacts with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which recruits pro-caspase-1 and regulates the maturation and secretion of interleukin (IL)-1β and IL-18. A recent study showed that inflammasome activation contributes to lung inflammation and fibrogenesis during IPF. In the current review, we discuss recent advances in our understanding of the DROSHA−miRNA−AIM2 inflammasome axis in the pathogenesis of IPF.
Published: 2020

50. Decreased NLRP3 inflammasome expression in aged lung may contribute to increased susceptibility to secondary Streptococcus pneumoniae infection

Author: Kristen T. Rooney, Maria Plataki, Dana Mitzel, Gena Lowry, Heather W. Stout-Delgado, and Soo Jung Cho
Subjects: 0301 basic medicine, Male, Aging, Inflammasomes, Interleukin-1beta, medicine.disease_cause, Biochemistry, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Endocrinology, Streptococcus pneumoniae, NLR Family, Pyrin Domain-Containing 3 Protein, Genetics, medicine, Animals, Molecular Biology, Lung, Mice, Inbred BALB C, Innate immune system, business.industry, Bacterial pneumonia, TLR9, Inflammasome, Cell Biology, Pneumonia, Pneumococcal, medicine.disease, Toll-Like Receptor 1, Immunity, Innate, respiratory tract diseases, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Toll-Like Receptor 6, TLR6, Toll-Like Receptor 9, Immunology, Pneumococcal pneumonia, Host-Pathogen Interactions, Female, business, 030215 immunology, medicine.drug
Abstract: Post-viral pneumococcal pneumonia is a leading morbidity and mortality in older patients (≥ 65 years of age). The goal of our current study is to understand the impact of chronological aging on innate immune responses to a secondary, post viral infection with Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using aged murine models of infection, our findings demonstrate increased morbidity and mortality in aged mice within 48 hours post secondary S. pneumoniae infection. Increased susceptibility of aged mice was associated with decreased TLR1, TLR6, and TLR9 mRNA expression and diminished IL1β mRNA expression. Examination of NLRP3 inflammasome expression illustrated decreased NLRP3 mRNA expression and decreased IL1β production in aged lung in response to secondary S. pneumoniae infection.
Published: 2017

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