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1. Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease

Author

Ariño, Silvia, Aguilar-Bravo, Beatriz, Coll, Mar, Lee, Woo-Yong, Peiseler, Moritz, Cantallops-Vilà, Paula, Sererols-Viñas, Laura, Martínez-García de la Torre, Raquel A., Martínez-Sánchez, Celia, Pedragosa, Jordi, Zanatto, Laura, Gratacós-Ginès, Jordi, Pose, Elisa, Blaya, Delia, Almodóvar, Xènia, Fernández-Fernández, María, Ruiz-Blázquez, Paloma, Lozano, Juan José, Affo, Silvia, Planas, Anna M., Ginès, Pere, Moles, Anna, Kubes, Paul, and Sancho-Bru, Pau

Published
2023
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3. Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever

Author

Jorch, Selina K., McNally, Annika, Berger, Philipp, Wolf, Jonas, Kaiser, Kim, Chetrusca Covash, Andrian, Robeck, Stefanie, Pastau, Isabell, Fehler, Olesja, Jauch-Speer, Saskia-L., Hermann, Sven, Schäfers, Michael, Van Gorp, Hanne, Kanneganti, Apurva, Dehoorne, Joke, Haerynck, Filomeen, Penco, Federica, Gattorno, Marco, Chae, Jae Jin, Kubes, Paul, Lamkanfi, Mohamed, Wullaert, Andy, Sperandio, Markus, Vogl, Thomas, Roth, Johannes, and Austermann, Judith

Published
2023
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4. A molecular map of murine lymph node blood vascular endothelium at single cell resolution.

Author

Brulois, Kevin, Rajaraman, Anusha, Szade, Agata, Nordling, Sofia, Bogoslowski, Ania, Dermadi, Denis, Rahman, Milladur, Kiefel, Helena, OHara, Edward, Koning, Jasper, Kawashima, Hiroto, Zhou, Bin, Vestweber, Dietmar, Red-Horse, Kristy, Mebius, Reina, Adams, Ralf, Kubes, Paul, Pan, Junliang, and Butcher, Eugene

Subjects
Animals, Base Sequence, Cell Movement, Endothelial Cells, Endothelium, Vascular, Female, Gene Expression Profiling, Homeostasis, Inflammation, Lymph Nodes, Lymphocytes, Lymphoid Tissue, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Myeloid Cells, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome
Abstract

Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.

Published
2020

12. Patients with COVID-19: in the dark-NETs of neutrophils

Author

Ackermann, Maximilian, Anders, Hans-Joachim, Bilyy, Rostyslav, Bowlin, Gary L., Daniel, Christoph, De Lorenzo, Rebecca, Egeblad, Mikala, Henneck, Timo, Hidalgo, Andrés, Hoffmann, Markus, Hohberger, Bettina, Kanthi, Yogendra, Kaplan, Mariana J., Knight, Jason S., Knopf, Jasmin, Kolaczkowska, Elzbieta, Kubes, Paul, Leppkes, Moritz, Mahajan, Aparna, Manfredi, Angelo A., Maueröder, Christian, Maugeri, Norma, Mitroulis, Ioannis, Muñoz, Luis E., Narasaraju, Teluguakula, Naschberger, Elisabeth, Neeli, Indira, Ng, Lai Guan, Radic, Marko Z., Ritis, Konstantinos, Rovere-Querini, Patrizia, Schapher, Mirco, Schauer, Christine, Simon, Hans-Uwe, Singh, Jeeshan, Skendros, Panagiotis, Stark, Konstantin, Stürzl, Michael, van der Vlag, Johan, Vandenabeele, Peter, Vitkov, Ljubomir, von Köckritz-Blickwede, Maren, Yanginlar, Cansu, Yousefi, Shida, Zarbock, Alexander, Schett, Georg, and Herrmann, Martin

Published
2021
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15. The lung is a host defense niche for immediate neutrophil-mediated vascular protection

Author

Yipp, Bryan G, Kim, Jung Hwan, Lima, Ronald, Zbytnuik, Lori D, Petri, Bjӧrn, Swanlund, Nick, Ho, May, Szeto, Vivian G, Tak, Tamar, Koenderman, Leo, Pickkers, Peter, Tool, Anton TJ, Kuijpers, Taco W, van den Berg, Timo K, Looney, Mark R, Krummel, Matthew F, and Kubes, Paul

Subjects
Sepsis, Lung, Prevention, Vaccine Related, Hematology, Biodefense, Infectious Diseases, Infection
Abstract

Bloodstream infection is a hallmark of sepsis, a medically emergent condition requiring rapid treatment. However, upregulation of host defense proteins through toll-like receptors and NFκB requires hours after endotoxin detection. Using confocal pulmonary intravital microscopy, we identified that the lung provides a TLR4-Myd88-and abl tyrosine kinase-dependent niche for immediate CD11b-dependent neutrophil responses to endotoxin and Gram-negative bloodstream pathogens. In an in vivo model of bacteremia, neutrophils crawled to and rapidly phagocytosed Escherichia coli sequestered to the lung endothelium. Therefore, the lung capillaries provide a vascular defensive niche whereby endothelium and neutrophils cooperate for immediate detection and capture of disseminating pathogens.

Published
2017

19. Peritoneal [GATA6.sup.+] macrophages function as a portal for Staphylococcus aureus dissemination

Author

Jorch, Selina K., Surewaard, Bas G.J., Hossain, Mokarram, Peiseler, Moritz, Deppermann, Carsten, Deng, Jennifer, Bogoslowski, Ania, van der Wal, Fardau, Omri, Abdelwahab, Hickey, Michael J., and Kubes, Paul

Subjects
Thermo Fisher Scientific Inc., Staphylococcus aureus infections, Bacteria, Macrophages, Staphylococcus aureus, Liver, Kidney diseases, Methicillin, Scientific equipment industry, Antibacterial agents, Vancomycin, Peritonitis, Health care industry
Abstract

Essentially all Staphylococcus aureus (S. aureus) bacteria that gain access to the circulation are plucked out of the bloodstream by the intravascular macrophages of the liver--the Kupffer cells. It is also thought that these bacteria are disseminated via the bloodstream to other organs. Our data show that S. aureus inside Kupffer cells grew and escaped across the mesothelium into the peritoneal cavity and immediately infected GATA-binding factor 6-positive (GATA6+) peritoneal cavity macrophages. These macrophages provided a haven for S. aureus, thereby delaying the neutrophilic response in the peritoneum by 48 hours and allowing dissemination to various peritoneal and retroperitoneal organs including the kidneys. In mice deficient in GATA6+ peritoneal macrophages, neutrophils infiltrated more robustly and reduced S. aureus dissemination. Antibiotics administered i.v. did not prevent dissemination into the peritoneum or to the kidneys, whereas peritoneal administration of vancomycin (particularly liposomal vancomycin with optimized intracellular penetrance capacity) reduced kidney infection and mortality, even when administered 24 hours after infection. These data indicate that GATA6+ macrophages within the peritoneal cavity are a conduit of dissemination for i.v. S. aureus, and changing the route of antibiotic delivery could provide a more effective treatment for patients with peritonitis- associated bacterial sepsis., Introduction In humans, Staphylococcus aureus (S. aureus) bacteremia is the most common serious bacterial blood infection globally. In the United Kingdom alone, approximately 12,500 cases each year are reported with [...]

Published
2019
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24. Author Correction: Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer

Author

Malehmir, Mohsen, Pfister, Dominik, Gallage, Suchira, Szydlowska, Marta, Inverso, Donato, Kotsiliti, Elena, Leone, Valentina, Peiseler, Moritz, Surewaard, Bas G. J., Rath, Dominik, Ali, Adnan, Wolf, Monika Julia, Drescher, Hannah, Healy, Marc E., Dauch, Daniel, Kroy, Daniela, Krenkel, Oliver, Kohlhepp, Marlene, Engleitner, Thomas, Olkus, Alexander, Sijmonsma, Tjeerd, Volz, Julia, Deppermann, Carsten, Stegner, David, Helbling, Patrick, Nombela-Arrieta, César, Rafiei, Anahita, Hinterleitner, Martina, Rall, Marcel, Baku, Florian, Borst, Oliver, Wilson, Caroline L., Leslie, Jack, O’Connor, Tracy, Weston, Christopher J., Chauhan, Abhishek, Adams, David H., Sheriff, Lozan, Teijeiro, Ana, Prinz, Marco, Bogeska, Ruzhica, Anstee, Natasha, Bongers, Malte N., Notohamiprodjo, Mike, Geisler, Tobias, Withers, Dominic J., Ware, Jerry, Mann, Derek A., Augustin, Hellmut G., Vegiopoulos, Alexandros, Milsom, Michael D., Rose, Adam J., Lalor, Patricia F., Llovet, Josep M., Pinyol, Roser, Tacke, Frank, Rad, Roland, Matter, Matthias, Djouder, Nabil, Kubes, Paul, Knolle, Percy A., Unger, Kristian, Zender, Lars, Nieswandt, Bernhard, Gawaz, Meinrad, Weber, Achim, and Heikenwalder, Mathias

Published
2022
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25. More friend than foe: the emerging role of neutrophils in tissue repair

Author

Peiseler, Moritz and Kubes, Paul

Subjects
Inflammation -- Health aspects, Infection -- Health aspects, Pathogenic microorganisms, Novels, Health care industry
Abstract

Neutrophils are the most abundant immune cells in humans and serve as first responders to a myriad of host perturbations. Equipped with a plethora of antimicrobial molecules, neutrophils invade sites of inflammation to eradicate pathogens and clear debris. Traditionally, neutrophils were thought to cause collateral tissue damage before dying at the site. However, the presence of neutrophil infiltration into sterile injuries (in the absence of infections) suggests additional roles for these cells. Now, the view of neutrophils as indiscriminate killers seems to be changing as evolving evidence suggests that neutrophils actively orchestrate resolution of inflammation and contribute to tissue repair. Novel concepts include the idea that neutrophils are key to revascularization and subsequently reverse-transmigrate back to the vasculature, actively leaving sites of tissue damage to re-home to functional niches in the lung and bone marrow. This Review scrutinizes the role of neutrophils in tissue damage and repair, discussing recent findings and raising unresolved questions around this intriguing immune cell., Introduction Neutrophils are the most abundant immune cells, constituting about 60% to 70% of all leukocytes in human blood (1, 2). Neutrophils act as the first responders of the innate [...]

Published
2019
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26. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer

Author

Malehmir, Mohsen, Pfister, Dominik, Gallage, Suchira, Szydlowska, Marta, Inverso, Donato, Kotsiliti, Elena, Leone, Valentina, Peiseler, Moritz, Surewaard, Bas G. J., Rath, Dominik, Ali, Adnan, Wolf, Monika Julia, Drescher, Hannah, Healy, Marc E., Dauch, Daniel, Kroy, Daniela, Krenkel, Oliver, Kohlhepp, Marlene, Engleitner, Thomas, Olkus, Alexander, Sijmonsma, Tjeerd, Volz, Julia, Deppermann, Carsten, Stegner, David, Helbling, Patrick, Nombela-Arrieta, César, Rafiei, Anahita, Hinterleitner, Martina, Rall, Marcel, Baku, Florian, Borst, Oliver, Wilson, Caroline L., Leslie, Jack, O’Connor, Tracy, Weston, Christopher J., Chauhan, Abhishek, Adams, David H., Sheriff, Lozan, Teijeiro, Ana, Prinz, Marco, Bogeska, Ruzhica, Anstee, Natasha, Bongers, Malte N., Notohamiprodjo, Mike, Geisler, Tobias, Withers, Dominic J., Ware, Jerry, Mann, Derek A., Augustin, Hellmut G., Vegiopoulos, Alexandros, Milsom, Michael D., Rose, Adam J., Lalor, Patricia F., Llovet, Josep M., Pinyol, Roser, Tacke, Frank, Rad, Roland, Matter, Matthias, Djouder, Nabil, Kubes, Paul, Knolle, Percy A., Unger, Kristian, Zender, Lars, Nieswandt, Bernhard, Gawaz, Meinrad, Weber, Achim, and Heikenwalder, Mathias

Published
2019
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27. To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps

Author

Boeltz, Sebastian, Amini, Poorya, Anders, Hans-Joachim, Andrade, Felipe, Bilyy, Rostyslav, Chatfield, Simon, Cichon, Iwona, Clancy, Danielle M., Desai, Jyaysi, Dumych, Tetiana, Dwivedi, Nishant, Gordon, Rachael Ann, Hahn, Jonas, Hidalgo, Andrés, Hoffmann, Markus H., Kaplan, Mariana J., Knight, Jason S., Kolaczkowska, Elzbieta, Kubes, Paul, Leppkes, Moritz, Manfredi, Angelo A., Martin, Seamus J., Maueröder, Christian, Maugeri, Norma, Mitroulis, Ioannis, Munoz, Luis E., Nakazawa, Daigo, Neeli, Indira, Nizet, Victor, Pieterse, Elmar, Radic, Marko Z, Reinwald, Christiane, Ritis, Konstantinos, Rovere-Querini, Patrizia, Santocki, Michal, Schauer, Christine, Schett, Georg, Shlomchik, Mark Jay, Simon, Hans-Uwe, Skendros, Panagiotis, Stojkov, Darko, Vandenabeele, Peter, Berghe, Tom Vanden, van der Vlag, Johan, Vitkov, Ljubomir, von Köckritz-Blickwede, Maren, Yousefi, Shida, Zarbock, Alexander, and Herrmann, Martin

Published
2019
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34. Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury

Author

Lau, Arthur, Chung, Hyunjae, Komada, Takanori, Platnich, Jaye M., Sandall, Christina F., Choudhury, Saurav Roy, Chun, Justin, Naumenko, Victor, Surewaard, Bas G.J., Nelson, Michelle C., Ulke-Lemee, Annegret, Beck, Paul L., Benediktsson, Hallgrimur, Jevnikar, Anthony M., Snelgrove, Sarah L., Hickey, Michael J., Senger, Donna L., James, Matthew T., Macdonald, Justin A., Kubes, Paul, Jenne, Craig N., and Muruve, Daniel A.

Subjects
Kidney failure -- Genetic aspects -- Drug therapy, Radiography -- Usage, Contrast media -- Dosage and administration, Health care industry
Abstract

Radiographic contrast agents cause acute kidney injury (AKI), yet the underlying pathogenesis is poorly understood. Nod-like receptor pyrin containing 3-deficient (Nlrp3-deficient) mice displayed reduced epithelial cell injury and inflammation in the kidney in a model of contrast-induced AKI (CI-AKI). Unexpectedly, contrast agents directly induced tubular epithelial cell death in vitro that was not dependent on Nlrp3. Rather, contrast agents activated the canonical Nlrp3 inflammasome in macrophages. Intravital microscopy revealed diatrizoate (DTA) uptake within minutes in perivascular [CX.sub.3][CR1.sup.+] resident phagocytes in the kidney. Following rapid filtration into the tubular luminal space, DTA was reabsorbed and concentrated in tubular epithelial cells via the brush border enzyme dipeptidase-1 in volume-depleted but not euvolemic mice. [LysM-GFP.sup.+] macrophages recruited to the kidney interstitial space ingested contrast material transported from the urine via direct interactions with tubules. CI-AKI was dependent on resident renal phagocytes, IL-1, leukocyte recruitment, and dipeptidase-1. Levels of the inflammasome-related urinary biomarkers IL-18 and caspase-1 were increased immediately following contrast administration in patients undergoing coronary angiography, consistent with the acute renal effects observed in mice. Taken together, these data show that CI-AKI is a multistep process that involves immune surveillance by resident and infiltrating renal phagocytes, Nlrp3-dependent inflammation, and the tubular reabsorption of contrast via dipeptidase-1., Introduction Contrast-induced acute kidney injury (CI-AKI) is caused by iodinated contrast media for diagnostic imaging (1). Most patients with normal kidney function who receive contrast will not experience any renal [...]

Published
2018
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35. Human skin commensals augment Staphylococcus aureus pathogenesis

Author

Boldock, Emma, Surewaard, Bas G. J., Shamarina, Daria, Na, Manli, Fei, Ying, Ali, Abukar, Williams, Alexander, Pollitt, Eric J. G., Szkuta, Piotr, Morris, Paul, Prajsnar, Tomasz K., McCoy, Kathy D., Jin, Tao, Dockrell, David H., van Strijp, Jos A. G., Kubes, Paul, Renshaw, Stephen A., and Foster, Simon J.

Published
2018
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38. Bispecific antibody targets multiple pseudomonas aeruginosa evasion mechanisms in the lung vasculature

Author

Thanabalasuriar, Ajitha, Surewaard, Bas G.J., Willson, Michelle E., Neupane, Arpan S., Stover, Charles K., Warrener, Paul, Wilson, George, Keller, Ashley E., Sellman, Bret R., DiGiandomenico, Antonio, and Kubes, Paul

Subjects
Antibodies -- Health aspects -- Analysis, Lung diseases -- Prevention, Pseudomonas aeruginosa -- Health aspects -- Analysis, Health care industry
Abstract

Pseudomonas aeruginosa is a major cause of severe infections that lead to bacteremia and high patient mortality. P. aeruginosa has evolved numerous evasion and subversion mechanisms that work in concert to overcome immune recognition and effector functions in hospitalized and immunosuppressed individuals. Here, we have used multilaser spinning-disk intravital microscopy to monitor the blood-borne stage in a murine bacteremic model of P. aeruginosa infection. P. aeruginosa adhered avidly to lung vasculature, where patrolling neutrophils and other immune cells were virtually blind to the pathogen's presence. This cloaking phenomenon was attributed to expression of Psl exopolysaccharide. Although an antiPsl mAb activated complement and enhanced neutrophil recognition of P. aeruginosa, neutrophil-mediated clearance of the pathogen was suboptimal owing to a second subversion mechanism, namely the type 3 secretion (T3S) injectisome. Indeed, T3S prevented phagosome acidification and resisted killing inside these compartments. Antibody-mediated inhibition of the T3S protein PcrV did not enhance bacterial phagocytosis but did enhance killing of the few bacteria ingested by neutrophils. A bispecific mAb targeting both Psl and PcrV enhanced neutrophil uptake of P. aeruginosa and also greatly increased inhibition of T3S function, allowing for phagosome acidification and bacterial killing. These data highlight the need to block multiple evasion and subversion mechanisms in tandem to kill P. aeruginosa., Introduction Pseudomonas aeruginosa is an important opportunistic bacterial pathogen that causes life-threatening infections in critically ill and immunocompromised individuals. It is one of the most common causes of Gram-negative pneumonia [...]

Published
2017
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39. An emerging role for neutrophil extracellular traps in noninfectious disease

Author

Jorch, Selina K and Kubes, Paul

Subjects
Chronic diseases -- Development and progression -- Care and treatment, Phagocytes -- Health aspects, Immune response -- Observations, Biological sciences, Health
Abstract

The production of neutrophil extracellular traps (NETs) is a process that enables neutrophils to help catch and kill bacteria. However, increasing evidence suggests that this process might also occur in noninfectious, sterile inflammation. In this Review, we describe the role of NETosis in autoimmunity, coagulation, acute injuries and cancer, and discuss NETs as potential therapeutic targets. Furthermore, we consider whether extracellular DNA is always detrimental in sterile inflammation and whether the source is always NETs., Author(s): Selina K Jorch [1]; Paul Kubes (corresponding author) [1, 2] Neutrophil extracellular traps (NETs) are structures of chromatin filaments coated with histones, proteases and granular and cytosolic proteins, and [...]

Published
2017
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40. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity

Author

Fowler, Benjamin J., Gelfand, Bradley D., Kim, Younghee, Kerur, Nagaraj, Tarallo, Valeria, Hirano, Yoshio, Amarnath, Shoba, Fowler, Daniel H., Radwan, Marta, Young, Mark T., Pittman, Keir, Kubes, Paul, Agarwal, Hitesh K., Parang, Keykavous, Hinton, David R., Bastos-Carvalho, Ana, Li, Shengjian, Yasuma, Tetsuhiro, Mizutani, Takeshi, Yasuma, Reo, Wright, Charles, and Ambati, Jayakrishna

Published
2014

45. Closed Or Open after Source Control Laparotomy for Severe Complicated Intra-Abdominal Sepsis (the COOL trial): study protocol for a randomized controlled trial

Author

Kirkpatrick, Andrew W., Coccolini, Federico, Ansaloni, Luca, Roberts, Derek J., Tolonen, Matti, McKee, Jessica L., Leppaniemi, Ari, Faris, Peter, Doig, Christopher J., Catena, Fausto, Fabian, Timothy, Jenne, Craig N., Chiara, Osvaldo, Kubes, Paul, Manns, Braden, Kluger, Yoram, Fraga, Gustavo P., Pereira, Bruno M., Diaz, Jose J., Sugrue, Michael, Moore, Ernest E., Ren, Jianan, Ball, Chad G., Coimbra, Raul, Balogh, Zsolt J., Abu-Zidan, Fikri M., Dixon, Elijah, Biffl, Walter, MacLean, Anthony, Ball, Ian, Drover, John, McBeth, Paul B., Posadas-Calleja, Juan G., Parry, Neil G., Di Saverio, Salomone, Ordonez, Carlos A., Xiao, Jimmy, Sartelli, Massimo, and for The Closed Or Open after Laparotomy (COOL) after Source Control for Severe Complicated Intra-Abdominal Sepsis Investigators

Published
2018
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46. Getting the invite list right: a discussion of sepsis severity scoring systems in severe complicated intra-abdominal sepsis and randomized trial inclusion criteria

Author

Tolonen, Matti, Coccolini, Federico, Ansaloni, Luca, Sartelli, Massimo, Roberts, Derek J., McKee, Jessica L., Leppaniemi, Ari, Doig, Christopher J., Catena, Fausto, Fabian, Timothy, Jenne, Craig N., Chiara, Osvaldo, Kubes, Paul, Kluger, Yoram, Fraga, Gustavo P., Pereira, Bruno M., Diaz, Jose J., Sugrue, Michael, Moore, Ernest E., Ren, Jianan, Ball, Chad G., Coimbra, Raul, Dixon, Elijah, Biffl, Walter, MacLean, Anthony, McBeth, Paul B., Posadas-Calleja, Juan G., Di Saverio, Salomone, Xiao, Jimmy, Kirkpatrick, Andrew W., and From the Closed Or Open after Laparotomy (COOL) for Source Control in Severe Complicated Intra-Abdominal Sepsis Investigators

Published
2018
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