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1. Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII

Author

Athena L. Russell, Chengyu Prince, Taran S. Lundgren, Kristopher A. Knight, Gabriela Denning, Jordan S. Alexander, Jaquelyn T. Zoine, H. Trent Spencer, Shanmuganathan Chandrakasan, and Christopher B. Doering

Subjects
non-genotoxic conditioning, antibody conditioning, immunotoxin, antibody-drug conjugate, hematopoietic stem cell transplantation, ex vivo lentiviral vector gene therapy, Genetics, QH426-470, Cytology, QH573-671
Abstract

Hematopoietic stem and progenitor cell (HSPC) lentiviral gene therapy is a promising strategy toward a lifelong cure for hemophilia A (HA). The primary risks associated with this approach center on the requirement for pre-transplantation conditioning necessary to make space for, and provide immune suppression against, stem cells and blood coagulation factor VIII, respectively. Traditional conditioning agents utilize genotoxic mechanisms of action, such as DNA alkylation, that increase risk of sterility, infection, and developing secondary malignancies. In the current study, we describe a non-genotoxic conditioning protocol using an immunotoxin targeting CD117 (c-kit) to achieve endogenous hematopoietic stem cell depletion and a cocktail of monoclonal antibodies to provide transient immune suppression against the transgene product in a murine HA gene therapy model. This strategy provides high-level engraftment of hematopoietic stem cells genetically modified ex vivo using recombinant lentiviral vector (LV) encoding a bioengineered high-expression factor VIII variant, termed ET3. Factor VIII procoagulant activity levels were durably elevated into the normal range and phenotypic correction achieved. Furthermore, no immunological rejection or development of anti-ET3 immunity was observed. These preclinical data support clinical translation of non-genotoxic antibody-based conditioning in HSPC LV gene therapy for HA.

Published
2021
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2. Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway

Author

Seema R. Patel, Taran S. Lundgren, Wallace Hunter Baldwin, Courtney Cox, Ernest T. Parker, John F. Healey, Ryan P. Jajosky, Patricia E. Zerra, Cassandra D. Josephson, Christopher B. Doering, Sean R. Stowell, and Shannon L. Meeks

Subjects
hemophilia A, germinal center, B cells, neutralizing antibodies (inhibitors), extrafollicular pathway, Immunologic diseases. Allergy, RC581-607
Abstract

Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. While some patients produce persistent low or high inhibitor titers, others generate a transient response. Moreover, FVIII reactive memory B cells are only detectable in some patients with sustained inhibitor titers. The determinants regulating the type of immune response a patient develops, let alone how the immune response differs in these patients remains incompletely understood. One hypothesis is that polymorphisms within immunoregulatory genes alter the underlying immune response to FVIII, and thereby the inhibitor response. Consistent with this, studies report that inhibitor titers to FVIII differ in animals with the same F8 pathogenic variant but completely distinct backgrounds; though, how these genetic disparities affect the immune response to FVIII remains to be investigated. Given this, we sought to mechanistically dissect how genetics impact the underlying immune response to FVIII. In particular, as the risk of producing inhibitors is weakly associated with differences in HLA, we hypothesized that genetic factors other than HLA influence the immune response to FVIII and downstream inhibitor formation. Our data demonstrate that FVIII deficient mice encoding the same MHC and F8 variant produce disparate inhibitor titers, and that the type of inhibitor response formed associates with the ability to generate GCs. Interestingly, the formation of antibodies through a GC or non-GC pathway does not appear to be due to differences in CD4 T cell immunity, as the CD4 T cell response to an immunodominant epitope in FVIII was similar in these mice. These results indicate that genetics can impact the process by which inhibitors develop and may in part explain the apparent propensity of patients to form distinct inhibitor responses. Moreover, these data highlight an underappreciated immunological pathway of humoral immunity to FVIII and lay the groundwork for identification of biomarkers for the development of approaches to tolerize against FVIII.

Published
2022
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3. The Immune Response to the fVIII Gene Therapy in Preclinical Models

Author

Seema R. Patel, Taran S. Lundgren, H. Trent Spencer, and Christopher B. Doering

Subjects
gene therapy, hemophilia A, inhibitors, lentiviral (LV) vector, adeno-associated viral vectors, hematopoietic (stem) cells, Immunologic diseases. Allergy, RC581-607
Abstract

Neutralizing antibodies to factor VIII (fVIII), referred to as “inhibitors,” remain the most challenging complication post-fVIII replacement therapy. Preclinical development of novel fVIII products involves studies incorporating hemophilia A (HA) and wild-type animal models. Though immunogenicity is a critical aspect of preclinical pharmacology studies, gene therapy studies tend to focus on fVIII expression levels without major consideration for immunogenicity. Therefore, little clarity exists on whether preclinical testing can be predictive of clinical immunogenicity risk. Despite this, but perhaps due to the potential for transformative benefits, clinical gene therapy trials have progressed rapidly. In more than two decades, no inhibitors have been observed. However, all trials are conducted in previously treated patients without a history of inhibitors. The current review thus focuses on our understanding of preclinical immunogenicity for HA gene therapy candidates and the potential indication for inhibitor treatment, with a focus on product- and platform-specific determinants, including fVIII transgene sequence composition and tissue/vector biodistribution. Currently, the two leading clinical gene therapy vectors are adeno-associated viral (AAV) and lentiviral (LV) vectors. For HA applications, AAV vectors are liver-tropic and employ synthetic, high-expressing, liver-specific promoters. Factors including vector serotype and biodistribution, transcriptional regulatory elements, transgene sequence, dosing, liver immunoprivilege, and host immune status may contribute to tipping the scale between immunogenicity and tolerance. Many of these factors can also be important in delivery of LV-fVIII gene therapy, especially when delivered intravenously for liver-directed fVIII expression. However, ex vivo LV-fVIII targeting and transplantation of hematopoietic stem and progenitor cells (HSPC) has been demonstrated to achieve durable and curative fVIII production without inhibitor development in preclinical models. A critical variable appears to be pre-transplantation conditioning regimens that suppress and/or ablate T cells. Additionally, we and others have demonstrated the potential of LV-fVIII HSPC and liver-directed AAV-fVIII gene therapy to eradicate pre-existing inhibitors in murine and canine models of HA, respectively. Future preclinical studies will be essential to elucidate immune mechanism(s) at play in the context of gene therapy for HA, as well as strategies for preventing adverse immune responses and promoting immune tolerance even in the setting of pre-existing inhibitors.

Published
2020
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4. Delayed Diagnosis of Pharyngeal Perforation following Exploding Tyre Blast Barotrauma

Author

Samantha M. Field, Joseph G. Manjaly, S. Krishan Ramdoo, Huw A. S. Jones, and Taran S. Tatla

Subjects
Otorhinolaryngology, RF1-547
Abstract

Introduction. Pharyngoesophageal perforation secondary to barotrauma is a rare phenomenon that can have serious complications if identified late. It is challenging to detect due to nonspecific symptoms. We present a case in which detection proved difficult leading to delayed diagnosis. Case Report. A 27-year-old mechanic presented with haemoptysis, dysphonia, and odynophagia after a car tyre exploded in his face. Flexible nasoendoscopy (FNE) revealed blood in the pharynx, thought to represent mucosal haemorrhage. Initial treatment consisted of IV dexamethasone and antibiotics. After 3 days, odynophagia persisted prompting a CT scan. This revealed a defect in the posterior hypopharynx and surgical emphysema in the deep neck tissues. Contrast swallow confirmed posterior hypopharyngeal leak. NG feeding was commenced until repeated contrast swallow confirmed resolution of the defect. Discussion. Prompt nonsurgical management of pharyngoesophageal perforation has good outcomes but untreated perforation can have serious complications. FNE should be performed routinely, but only a contrast swallow can diagnose a functional perforation. Clinicians should have a high index of clinical suspicion when patients present with barotrauma and odynophagia. Patients should be kept nil by mouth until perforation has been excluded. Conclusion. When faced with cases of facial barotrauma, clinicians should have a low threshold for further imaging to exclude pharyngoesophageal perforation.

Published
2014
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6. Evaluating the Sum of Eye and Motor Components of the Glasgow Coma Score As a Predictor of Extubation Failure in Patients with Acute Brain Injury

Author

Taran, S, Perrot, B, Angriman, F, Cinotti, R, Abback, P, Codorniu, A, Citerio, G, Ludovica Sala, V, Astuto, M, Tringali, E, Alampi, D, Rocco, M, Giuseppina Maugeri, J, Bellissima, A, Filippini, M, Lazzeri, N, Cortegiani, A, Ippolito, M, Robba, C, Battaglini, D, Biston, P, Fathi Al-Gharyani, M, Chabanne, R, Astier, L, Soyer, B, Gaugain, S, Zimmerli, A, Pietsch, U, Filipovic, M, Brandi, G, Bicciato, G, Serrano, A, Monleon, B, Van Vliet, P, Marcel Gerretsen, B, Xochitl Ortiz-Macias, I, Oto, J, Enomoto, N, Matsuda, T, Masui, N, Garcon, P, Zarka, J, Vermeijden, W, Daniel Cornet, A, Reyes Inurrigarro, S, Cirino Lara Dominguez, R, Mercedes Bellini, M, Milagros Gomez Haedo, M, Lamot, L, Orquera, J, Biais, M, Georges, D, Baronia, A, Carlos Miranda-Ackerman, R, Jose Barbosa-Camacho, F, Porter, J, Lopez-Morales, M, Geeraerts, T, Compagnon, B, Perez-Torres, D, Prol-Silva, E, Basheer Yahya, H, Khaled, A, Ghula, M, Neville Andrea, C, Maria Daniela, P, Deana, C, Vetrugno, L, Rivera Chavez, M, Mendoza Trujillo, R, Legros, V, Brochet, B, Huet, O, Geslain, M, Van Der Jagt, M, Van Steenkiste, J, Ahmed, H, Edward Coombs, A, Welbourne, J, Velarde Pineda, A, Nubert Castillo, V, Azab, M, Azzam, A, Paul Van Meenen, D, Adrian Gasca, G, Arellano, A, Galicia-Espinosa, F, Carlos Garcia-Ramos, J, Yadav, G, Kumar Jha, A, Robert-Edan, V, Rodie-Talbere, P, Jain, G, Panda, S, Agarwal, S, Deewan, Y, Tariq Reza, S, Hossain, M, Papadas, C, Chantziara, V, Sklavou, C, Hourmant, Y, Grillot, N, Pirracchio, R, Akkari, A, Abdelaty, M, Hashim, A, Launey, Y, Masseret, E, Lasocki, S, Gergaud, S, Mouclier, N, Saxena, S, Agrawal, A, Bedanta Mishra, S, Samal, S, Cesar Mijangos, J, Haenggi, M, Gurjar, M, Schultz, M, Kaye, C, Agustin Godoy, D, Alvarez, P, Ioakeimidou, A, Ueno, Y, Badenes, R, Suei Elbuzidi, A, Piagnerelli, M, Elhadi, M, Atef Azab, M, Catherine Digitale, J, Fong, N, Campos Cerda, R, De La Torre Peredo, N, David Stevens, R, Taran S., Perrot B., Angriman F., Cinotti R., Abback P. -S., Codorniu A., Citerio G., Ludovica Sala V., Astuto M., Tringali E., Alampi D., Rocco M., Giuseppina Maugeri J., Bellissima A., Filippini M., Lazzeri N., Cortegiani A., Ippolito M., Robba C., Battaglini D., Biston P., Fathi Al-Gharyani M., Chabanne R., Astier L., Soyer B., Gaugain S., Zimmerli A., Pietsch U., Filipovic M., Brandi G., Bicciato G., Serrano A., Monleon B., Van Vliet P., Marcel Gerretsen B., Xochitl Ortiz-Macias I., Oto J., Enomoto N., Matsuda T., Masui N., Garcon P., Zarka J., Vermeijden W. J., Daniel Cornet A., Reyes Inurrigarro S., Cirino Lara Dominguez R., Mercedes Bellini M., Milagros Gomez Haedo M., Lamot L., Orquera J., Biais M., Georges D., Baronia A., Carlos Miranda-Ackerman R., Jose Barbosa-Camacho F., Porter J., Lopez-Morales M., Geeraerts T., Compagnon B., Perez-Torres D., Prol-Silva E., Basheer Yahya H., Khaled A., Ghula M., Neville Andrea C., Maria Daniela P., Deana C., Vetrugno L., Rivera Chavez M. J., Mendoza Trujillo R., Legros V., Brochet B., Huet O., Geslain M., Van Der Jagt M., Van Steenkiste J., Ahmed H., Edward Coombs A., Welbourne J., Velarde Pineda A. A., Nubert Castillo V. H., Azab M. A., Azzam A. Y., Paul Van Meenen D. M., Adrian Gasca G., Arellano A., Galicia-Espinosa F., Carlos Garcia-Ramos J., Yadav G., Kumar Jha A., Robert-Edan V., Rodie-Talbere P. -A., Jain G., Panda S., Agarwal S., Deewan Y., Tariq Reza S., Hossain M. M., Papadas C., Chantziara V., Sklavou C., Hourmant Y., Grillot N., Pirracchio R., Akkari A., Abdelaty M., Hashim A., Launey Y., Masseret E., Lasocki S., Gergaud S., Mouclier N., Saxena S., Agrawal A., Bedanta Mishra S., Samal S., Cesar Mijangos J., Haenggi M., Gurjar M., Schultz M. J., Kaye C., Agustin Godoy D., Alvarez P., Ioakeimidou A., Ueno Y., Badenes R., Suei Elbuzidi A. A., Piagnerelli M., Elhadi M., Atef Azab M., Catherine Digitale J., Fong N., Campos Cerda R., De La Torre Peredo N., David Stevens R., Taran, S, Perrot, B, Angriman, F, Cinotti, R, Abback, P, Codorniu, A, Citerio, G, Ludovica Sala, V, Astuto, M, Tringali, E, Alampi, D, Rocco, M, Giuseppina Maugeri, J, Bellissima, A, Filippini, M, Lazzeri, N, Cortegiani, A, Ippolito, M, Robba, C, Battaglini, D, Biston, P, Fathi Al-Gharyani, M, Chabanne, R, Astier, L, Soyer, B, Gaugain, S, Zimmerli, A, Pietsch, U, Filipovic, M, Brandi, G, Bicciato, G, Serrano, A, Monleon, B, Van Vliet, P, Marcel Gerretsen, B, Xochitl Ortiz-Macias, I, Oto, J, Enomoto, N, Matsuda, T, Masui, N, Garcon, P, Zarka, J, Vermeijden, W, Daniel Cornet, A, Reyes Inurrigarro, S, Cirino Lara Dominguez, R, Mercedes Bellini, M, Milagros Gomez Haedo, M, Lamot, L, Orquera, J, Biais, M, Georges, D, Baronia, A, Carlos Miranda-Ackerman, R, Jose Barbosa-Camacho, F, Porter, J, Lopez-Morales, M, Geeraerts, T, Compagnon, B, Perez-Torres, D, Prol-Silva, E, Basheer Yahya, H, Khaled, A, Ghula, M, Neville Andrea, C, Maria Daniela, P, Deana, C, Vetrugno, L, Rivera Chavez, M, Mendoza Trujillo, R, Legros, V, Brochet, B, Huet, O, Geslain, M, Van Der Jagt, M, Van Steenkiste, J, Ahmed, H, Edward Coombs, A, Welbourne, J, Velarde Pineda, A, Nubert Castillo, V, Azab, M, Azzam, A, Paul Van Meenen, D, Adrian Gasca, G, Arellano, A, Galicia-Espinosa, F, Carlos Garcia-Ramos, J, Yadav, G, Kumar Jha, A, Robert-Edan, V, Rodie-Talbere, P, Jain, G, Panda, S, Agarwal, S, Deewan, Y, Tariq Reza, S, Hossain, M, Papadas, C, Chantziara, V, Sklavou, C, Hourmant, Y, Grillot, N, Pirracchio, R, Akkari, A, Abdelaty, M, Hashim, A, Launey, Y, Masseret, E, Lasocki, S, Gergaud, S, Mouclier, N, Saxena, S, Agrawal, A, Bedanta Mishra, S, Samal, S, Cesar Mijangos, J, Haenggi, M, Gurjar, M, Schultz, M, Kaye, C, Agustin Godoy, D, Alvarez, P, Ioakeimidou, A, Ueno, Y, Badenes, R, Suei Elbuzidi, A, Piagnerelli, M, Elhadi, M, Atef Azab, M, Catherine Digitale, J, Fong, N, Campos Cerda, R, De La Torre Peredo, N, David Stevens, R, Taran S., Perrot B., Angriman F., Cinotti R., Abback P. -S., Codorniu A., Citerio G., Ludovica Sala V., Astuto M., Tringali E., Alampi D., Rocco M., Giuseppina Maugeri J., Bellissima A., Filippini M., Lazzeri N., Cortegiani A., Ippolito M., Robba C., Battaglini D., Biston P., Fathi Al-Gharyani M., Chabanne R., Astier L., Soyer B., Gaugain S., Zimmerli A., Pietsch U., Filipovic M., Brandi G., Bicciato G., Serrano A., Monleon B., Van Vliet P., Marcel Gerretsen B., Xochitl Ortiz-Macias I., Oto J., Enomoto N., Matsuda T., Masui N., Garcon P., Zarka J., Vermeijden W. J., Daniel Cornet A., Reyes Inurrigarro S., Cirino Lara Dominguez R., Mercedes Bellini M., Milagros Gomez Haedo M., Lamot L., Orquera J., Biais M., Georges D., Baronia A., Carlos Miranda-Ackerman R., Jose Barbosa-Camacho F., Porter J., Lopez-Morales M., Geeraerts T., Compagnon B., Perez-Torres D., Prol-Silva E., Basheer Yahya H., Khaled A., Ghula M., Neville Andrea C., Maria Daniela P., Deana C., Vetrugno L., Rivera Chavez M. J., Mendoza Trujillo R., Legros V., Brochet B., Huet O., Geslain M., Van Der Jagt M., Van Steenkiste J., Ahmed H., Edward Coombs A., Welbourne J., Velarde Pineda A. A., Nubert Castillo V. H., Azab M. A., Azzam A. Y., Paul Van Meenen D. M., Adrian Gasca G., Arellano A., Galicia-Espinosa F., Carlos Garcia-Ramos J., Yadav G., Kumar Jha A., Robert-Edan V., Rodie-Talbere P. -A., Jain G., Panda S., Agarwal S., Deewan Y., Tariq Reza S., Hossain M. M., Papadas C., Chantziara V., Sklavou C., Hourmant Y., Grillot N., Pirracchio R., Akkari A., Abdelaty M., Hashim A., Launey Y., Masseret E., Lasocki S., Gergaud S., Mouclier N., Saxena S., Agrawal A., Bedanta Mishra S., Samal S., Cesar Mijangos J., Haenggi M., Gurjar M., Schultz M. J., Kaye C., Agustin Godoy D., Alvarez P., Ioakeimidou A., Ueno Y., Badenes R., Suei Elbuzidi A. A., Piagnerelli M., Elhadi M., Atef Azab M., Catherine Digitale J., Fong N., Campos Cerda R., De La Torre Peredo N., and David Stevens R.

Abstract

OBJECTIVES: To evaluate the association between the pre-extubation sum of eye and motor components of the Glasgow Coma Score (GCS-EM) and odds of extubation failure in patients with acute brain injury being liberated from mechanical ventilation. DESIGN: Secondary analysis of a prospective, multicenter observational study (ClinicalTrials.gov identifier NCT03400904). SETTING: Sixty-three hospital sites worldwide, with patient recruitment from January 2018 to November 2020. PATIENTS: One thousand one hundred fifty-two critically ill patients with acute brain injury, with a median age of 54 years, of whom 783 (68.0%) were male, 559 (48.5%) had traumatic brain injury, and 905 (78.6%) had a GCS-EM greater than 8 before extubation (scores range from 2 to 10). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: GCS-EM was computed in intubated patients on the day of extubation. The main outcome was extubation failure, defined as unplanned reintubation within 5 days of extubation. Analyses used multilevel logistic regression with adjustment for patient characteristics and a random intercept for hospital site. In the primary analysis, GCS-EM was not associated with extubation failure (odds ratio, 1.07 per additional point; 95% CI, 0.87-1.31). Findings were consistent in sensitivity analyses that: 1) used different adjustment covariates, 2) included a verbal estimate to derive an overall GCS, 3) accounted for missing data, 4) considered a 2-day time interval to define extubation failure, 5) accounted for competing risks, and 6) used a propensity score-based model. There was no association between GCS-EM and extubation outcome in subgroups defined by brain injury diagnosis or age. CONCLUSIONS: In this large, contemporary, multicenter cohort of patients with acute brain injury, we found no association between the GCS-EM and odds of extubation failure. However, few patients had a pre-extubation GCS-EM less than or equal to 8, and the possibility of a true prognostic association i

Published
2024

10. Research considerations for prospective studies of patients with coma and disorders of consciousness

Author

Tinti, L, Lawson, T, Molteni, E, Kondziella, D, Rass, V, Sharshar, T, Bodien, Y, Giacino, J, Mayer, S, Amiri, M, Muehlschlegel, S, Venkatasubba Rao, C, Vespa, P, Menon, D, Citerio, G, Helbok, R, Mcnett, M, Agarwal, S, Aiyagari, V, Akbari, Y, Albertson, A, Alexander, S, Alexandrov, A, Alkhachroum, A, Al-Mufti, F, Appavu, B, Gebrewold, M, Ayounb, M, Badenes, R, Bader, M, Badjiata, N, Balu, R, Barlow, B, Barra, M, Beekman, R, Beghi, E, Beqiri, E, Berlin, T, Bilotta, F, Bleck, T, Boerwinkle, V, Boly, M, Bonnel, A, Brazzi, L, Brown, E, Bulic, S, Caceres, E, Caceres, A, Cafiero, T, Carroll, E, Cediel, E, Chou, S, Claassen, J, Condie, C, Conti, A, Cosmas, K, Costa, P, Creutzfeldt, C, Dangayach, N, Dauri, M, Debicki, D, Degeorgia, M, Der-Nigoghossian, C, Desai, M, Dhar, R, Diringer, M, Durr, E, Edlow, B, Ercole, A, Estraneo, A, Falcone, G, Farrokh, S, Ferguson, A, Fernandez-Espejo, D, Fink, E, Fins, J, Foreman, B, Franchi, F, Frontera, J, Ganesan, R, Gaspard, N, Ghavam, A, Gibbons, C, Gilmore, E, Glustein, C, Gosseries, O, Green, T, Greer, D, Guanci, M, Gupta, D, Hahn, C, Hakimi, R, Hammond, F, Hanley, D, Hartings, J, Hassan, A, Hemphill, C, Da Cunha, A, Hinson, H, Hirsch, K, Hocker, S, Hu, P, Hu, X, Human, T, Hwang, D, Illes, J, Jaffa, M, James, M, Janas, A, Johnson, S, Jones, M, Jox, R, Kalanuria, A, Keller, E, Kennedy, L, Kennelly, M, Keogh, M, Kim, J, Kim, K, Kirsch, H, Kirschen, M, Ko, N, Kreitzer, N, Kromm, J, Kumar, A, Kurtz, P, Laureys, S, Lejeune, N, Lewis, A, Liang, J, Ling, G, Livesay, S, Luppi, A, Macdonald, J, Maddux, C, Mahanes, D, Mainali, S, Maldonado, N, Ribeiro, R, Mascia, L, Massimini, M, Mathur, R, Mccredie, V, Mejia-Mantilla, J, Mendoza, M, Meyfroidt, G, Mijangos, J, Moberg, D, Moheet, A, Montalenti, E, Monti, M, Morrison, C, Munar, M, Murtaugh, B, Naccache, L, Nagayama, M, Nairon, E, Nakagawa, T, Naldi, A, Narenthiran, G, Natarajan, G, Nemetsky, E, Newcombe, V, Nielsen, N, Niznick, N, Noronha-Falcão, F, Nyquist, P, Olson, D, Othman, M, Owen, A, Padayachy, L, Pajoumand, M, Park, S, Pergakis, M, Perry, H, Polizzotto, L, Pouratian, N, Spivack, M, Prisco, L, Provencio, J, Puglises, F, Puybasset, L, Rao, C, Rasmussen, L, Rasulo, F, Ray, B, Ricci, Z, Richardson, R, Shinotsuka, C, Robba, C, Robertson, C, Rohaut, B, Rolston, J, Romagnoli, S, Rosanova, M, Rosenthal, E, Rowe, S, Rubin, M, Russell, M, Silva, G, Sanz, L, Sarasso, S, Sarwal, A, Schiff, N, Schnakers, C, Seder, D, Shah, V, Shapiro-Rosenbaubm, A, Shapshak, A, Sharma, K, Shutter, L, Sitt, J, Slomine, B, Smetana, K, Smielewski, P, Smith, W, Stamatakis, E, Steinberg, A, Stevens, R, Suarez, J, Sung, G, Sussman, B, Taran, S, Mazzeo, A, Thibaut, A, Thompson, D, Threlkeld, Z, Toker, D, Torbey, M, Tosto, J, Trevick, S, Tsaousi, G, Turgeon, A, Udy, A, Varelas, P, Videtta, W, Voss, H, Vox, F, Wagner, A, Wahlster, S, Wainwright, M, Whyte, J, Witherspoon, B, Yakhkind, A, Yeager, S, Young, M, Zafar, S, Zafonte, R, Zahuranec, D, Zammit, C, Zhang, B, Ziai, W, Zimmerman, L, Zink, E, Tinti, Lorenzo, Lawson, Thomas, Molteni, Erika, Kondziella, Daniel, Rass, Verena, Sharshar, Tarek, Bodien, Yelena G, Giacino, Joseph T, Mayer, Stephan A, Amiri, Moshgan, Muehlschlegel, Susanne, Venkatasubba Rao, Chethan P, Vespa, Paul M, Menon, David K, Citerio, Giuseppe, Helbok, Raimund, McNett, Molly, Agarwal, Sachin, Aiyagari, Venkatesh, Akbari, Yama, Albertson, Asher, Alexander, Sheila, Alexandrov, Anne, Alkhachroum, Ayham, Al-Mufti, Fawaz, Amiri, Moshagan, Appavu, Brian, Gebrewold, Meron Awraris, Ayounb, Marc, Badenes, Rafael, Bader, Mary Kay, Badjiata, Neeraj, Balu, Ram, Barlow, Brooke, Barra, Megan, Beekman, Rachel, Beghi, Ettore, Beqiri, Erta, Berlin, Tracey, Bilotta, Federico, Bleck, Thomas, Bodien, Yelena, Boerwinkle, Varina, Boly, Melanie, Bonnel, Alexandra, Brazzi, Luca, Brown, Emery, Bulic, Sebina, Caceres, Eder, Caceres, Adrian, Cafiero, Tullio, Carroll, Elizabeth, Cediel, Emilio G, Chou, Sherry, Claassen, Jan, Condie, Chad, Conti, Alfredo, Cosmas, Katie, Costa, Paolo, Creutzfeldt, Claire, Dangayach, Neha, Dauri, Mario, Debicki, Derek, DeGeorgia, Michael, Der-Nigoghossian, Caroline, Desai, Masoom, Dhar, Rajat, Diringer, Michael, Durr, Emily, Edlow, Brian, Ercole, Ari, Estraneo, Anna, Falcone, Guido, Farrokh, Salia, Ferguson, Adam, Fernandez-Espejo, Davinia, Fink, Ericka, Fins, Joseph, Foreman, Brandon, Franchi, Federico, Frontera, Jennifer, Ganesan, Rishi, Gaspard, Nicolas, Ghavam, Ahmeneh, Giacino, Joseph, Gibbons, Christie, Gilmore, Emily, Glustein, Chavie, Gosseries, Olivia, Green, Theresa, Greer, David, Guanci, Mary, Gupta, Deepak, Hahn, Cecil, Hakimi, Ryan, Hammond, Flora, Hanley, Daniel F, Hartings, Jed, Hassan, Ahmed, Hemphill, Claude, Da Cunha, Arthur Henrique Galvão Bruno, Hinson, Holly, Hirsch, Karen, Hocker, Sarah, Hu, Peter, Hu, Xiao, Human, Theresa, Hwang, David, Illes, Judy, Jaffa, Matthew, James, Michael L, Janas, Anna, Johnson, Susan, Jones, Morgan, Jox, Ralf J, Kalanuria, Atul, Keller, Emanuela, Kennedy, Lori, Kennelly, Megan, Keogh, Maggie, Kim, Jenn, Kim, Keri, Kirsch, Hannah, Kirschen, Matthew, Ko, Nerissa, Kreitzer, Natalie, Kromm, Julie, Kumar, Abhay, Kurtz, Pedro, Laureys, Steven, Lejeune, Nicolas, Lewis, Ariane, Liang, John, Ling, Geoffrey, Livesay, Sarah, Luppi, Andrea, MacDonald, Jennifer, Maddux, Craig, Mahanes, Dea, Mainali, Shraddha, Maldonado, Nelson, Ribeiro, Rennan Martins, Mascia, Luciana, Massimini, Marcello, Mathur, Rohan, Mayer, Stephan, McCredie, Victoria, Mejia-Mantilla, Jorge, Mendoza, Michael, Menon, David, Meyfroidt, Geert, Mijangos, Julio, Moberg, Dick, Moheet, Asma, Montalenti, Elisa, Monti, Martin, Morrison, Chris, Munar, Marina, Murtaugh, Brooke, Naccache, Lionel, Nagayama, Masao, Nairon, Emerson, Nakagawa, Thomas, Naldi, Andrea, Narenthiran, Ganesalingam, Natarajan, Girija, Nemetsky, Esther, Newcombe, Virginia, Nielsen, Niklas, Niznick, Naomi, Noronha-Falcão, Filipa, Nyquist, Paul, Olson, DaiWai, Othman, Marwan, Owen, Adrian, Padayachy, Llewellyn, Pajoumand, Mehrnaz, Park, Soojin, Pergakis, Melissa, Perry, Heidi, Polizzotto, Len, Pouratian, Nader, Spivack, Marilyn Price, Prisco, Lara, Provencio, Javier, Puglises, Francesco, Puybasset, Louis, Rao, Chethan, Rasmussen, Lindsay, Rasulo, Frank, Ray, Bappaditya, Ricci, Zaccaria, Richardson, Risa, Shinotsuka, Cassia Righy, Robba, Chiara, Robertson, Courtney, Rohaut, Benjamin, Rolston, John, Romagnoli, Stefano, Rosanova, Mario, Rosenthal, Eric, Rowe, Shaun, Rubin, Michael, Russell, Mary Beth, Silva, Gisele Sampaio, Sanz, Leandro, Sarasso, Simone, Sarwal, Aarti, Schiff, Nicolas, Schnakers, Caroline, Seder, David, Shah, Vishank Arun, Shapiro-Rosenbaubm, Amy, Shapshak, Angela, Sharma, Kartavya, Sharma, Kumar Ajay, Shutter, Lori, Sitt, Jacobo, Slomine, Beth, Smetana, Keaton, Smielewski, Peter, Smith, Wade, Stamatakis, Emmanuel, Steinberg, Alexis, Stevens, Robert, Suarez, Jose, Sung, Gene, Sussman, Bethany, Taran, Shaurya, Mazzeo, Anna Teresa, Thibaut, Aurore, Thompson, David, Threlkeld, Zachary, Toker, Daniel, Torbey, Michel, Tosto, Jenna, Trevick, Stephen, Tsaousi, Georgia, Turgeon, Alexis, Udy, Andrew, Varelas, Panos, Vespa, Paul, Videtta, Walter, Voss, Henning, Vox, Ford, Wagner, Amy, Wahlster, Sarah, Wainwright, Mark, Whyte, John, Witherspoon, Briana, Yakhkind, Aleksandra (Sasha), Yeager, Susan, Young, Michael, Zafar, Sahar, Zafonte, Ross, Zahuranec, Darin, Zammit, Chris, Zhang, Bei, Ziai, Wendy, Zimmerman, Lara, Zink, Elizabeth, Tinti, L, Lawson, T, Molteni, E, Kondziella, D, Rass, V, Sharshar, T, Bodien, Y, Giacino, J, Mayer, S, Amiri, M, Muehlschlegel, S, Venkatasubba Rao, C, Vespa, P, Menon, D, Citerio, G, Helbok, R, Mcnett, M, Agarwal, S, Aiyagari, V, Akbari, Y, Albertson, A, Alexander, S, Alexandrov, A, Alkhachroum, A, Al-Mufti, F, Appavu, B, Gebrewold, M, Ayounb, M, Badenes, R, Bader, M, Badjiata, N, Balu, R, Barlow, B, Barra, M, Beekman, R, Beghi, E, Beqiri, E, Berlin, T, Bilotta, F, Bleck, T, Boerwinkle, V, Boly, M, Bonnel, A, Brazzi, L, Brown, E, Bulic, S, Caceres, E, Caceres, A, Cafiero, T, Carroll, E, Cediel, E, Chou, S, Claassen, J, Condie, C, Conti, A, Cosmas, K, Costa, P, Creutzfeldt, C, Dangayach, N, Dauri, M, Debicki, D, Degeorgia, M, Der-Nigoghossian, C, Desai, M, Dhar, R, Diringer, M, Durr, E, Edlow, B, Ercole, A, Estraneo, A, Falcone, G, Farrokh, S, Ferguson, A, Fernandez-Espejo, D, Fink, E, Fins, J, Foreman, B, Franchi, F, Frontera, J, Ganesan, R, Gaspard, N, Ghavam, A, Gibbons, C, Gilmore, E, Glustein, C, Gosseries, O, Green, T, Greer, D, Guanci, M, Gupta, D, Hahn, C, Hakimi, R, Hammond, F, Hanley, D, Hartings, J, Hassan, A, Hemphill, C, Da Cunha, A, Hinson, H, Hirsch, K, Hocker, S, Hu, P, Hu, X, Human, T, Hwang, D, Illes, J, Jaffa, M, James, M, Janas, A, Johnson, S, Jones, M, Jox, R, Kalanuria, A, Keller, E, Kennedy, L, Kennelly, M, Keogh, M, Kim, J, Kim, K, Kirsch, H, Kirschen, M, Ko, N, Kreitzer, N, Kromm, J, Kumar, A, Kurtz, P, Laureys, S, Lejeune, N, Lewis, A, Liang, J, Ling, G, Livesay, S, Luppi, A, Macdonald, J, Maddux, C, Mahanes, D, Mainali, S, Maldonado, N, Ribeiro, R, Mascia, L, Massimini, M, Mathur, R, Mccredie, V, Mejia-Mantilla, J, Mendoza, M, Meyfroidt, G, Mijangos, J, Moberg, D, Moheet, A, Montalenti, E, Monti, M, Morrison, C, Munar, M, Murtaugh, B, Naccache, L, Nagayama, M, Nairon, E, Nakagawa, T, Naldi, A, Narenthiran, G, Natarajan, G, Nemetsky, E, Newcombe, V, Nielsen, N, Niznick, N, Noronha-Falcão, F, Nyquist, P, Olson, D, Othman, M, Owen, A, Padayachy, L, Pajoumand, M, Park, S, Pergakis, M, Perry, H, Polizzotto, L, Pouratian, N, Spivack, M, Prisco, L, Provencio, J, Puglises, F, Puybasset, L, Rao, C, Rasmussen, L, Rasulo, F, Ray, B, Ricci, Z, Richardson, R, Shinotsuka, C, Robba, C, Robertson, C, Rohaut, B, Rolston, J, Romagnoli, S, Rosanova, M, Rosenthal, E, Rowe, S, Rubin, M, Russell, M, Silva, G, Sanz, L, Sarasso, S, Sarwal, A, Schiff, N, Schnakers, C, Seder, D, Shah, V, Shapiro-Rosenbaubm, A, Shapshak, A, Sharma, K, Shutter, L, Sitt, J, Slomine, B, Smetana, K, Smielewski, P, Smith, W, Stamatakis, E, Steinberg, A, Stevens, R, Suarez, J, Sung, G, Sussman, B, Taran, S, Mazzeo, A, Thibaut, A, Thompson, D, Threlkeld, Z, Toker, D, Torbey, M, Tosto, J, Trevick, S, Tsaousi, G, Turgeon, A, Udy, A, Varelas, P, Videtta, W, Voss, H, Vox, F, Wagner, A, Wahlster, S, Wainwright, M, Whyte, J, Witherspoon, B, Yakhkind, A, Yeager, S, Young, M, Zafar, S, Zafonte, R, Zahuranec, D, Zammit, C, Zhang, B, Ziai, W, Zimmerman, L, Zink, E, Tinti, Lorenzo, Lawson, Thomas, Molteni, Erika, Kondziella, Daniel, Rass, Verena, Sharshar, Tarek, Bodien, Yelena G, Giacino, Joseph T, Mayer, Stephan A, Amiri, Moshgan, Muehlschlegel, Susanne, Venkatasubba Rao, Chethan P, Vespa, Paul M, Menon, David K, Citerio, Giuseppe, Helbok, Raimund, McNett, Molly, Agarwal, Sachin, Aiyagari, Venkatesh, Akbari, Yama, Albertson, Asher, Alexander, Sheila, Alexandrov, Anne, Alkhachroum, Ayham, Al-Mufti, Fawaz, Amiri, Moshagan, Appavu, Brian, Gebrewold, Meron Awraris, Ayounb, Marc, Badenes, Rafael, Bader, Mary Kay, Badjiata, Neeraj, Balu, Ram, Barlow, Brooke, Barra, Megan, Beekman, Rachel, Beghi, Ettore, Beqiri, Erta, Berlin, Tracey, Bilotta, Federico, Bleck, Thomas, Bodien, Yelena, Boerwinkle, Varina, Boly, Melanie, Bonnel, Alexandra, Brazzi, Luca, Brown, Emery, Bulic, Sebina, Caceres, Eder, Caceres, Adrian, Cafiero, Tullio, Carroll, Elizabeth, Cediel, Emilio G, Chou, Sherry, Claassen, Jan, Condie, Chad, Conti, Alfredo, Cosmas, Katie, Costa, Paolo, Creutzfeldt, Claire, Dangayach, Neha, Dauri, Mario, Debicki, Derek, DeGeorgia, Michael, Der-Nigoghossian, Caroline, Desai, Masoom, Dhar, Rajat, Diringer, Michael, Durr, Emily, Edlow, Brian, Ercole, Ari, Estraneo, Anna, Falcone, Guido, Farrokh, Salia, Ferguson, Adam, Fernandez-Espejo, Davinia, Fink, Ericka, Fins, Joseph, Foreman, Brandon, Franchi, Federico, Frontera, Jennifer, Ganesan, Rishi, Gaspard, Nicolas, Ghavam, Ahmeneh, Giacino, Joseph, Gibbons, Christie, Gilmore, Emily, Glustein, Chavie, Gosseries, Olivia, Green, Theresa, Greer, David, Guanci, Mary, Gupta, Deepak, Hahn, Cecil, Hakimi, Ryan, Hammond, Flora, Hanley, Daniel F, Hartings, Jed, Hassan, Ahmed, Hemphill, Claude, Da Cunha, Arthur Henrique Galvão Bruno, Hinson, Holly, Hirsch, Karen, Hocker, Sarah, Hu, Peter, Hu, Xiao, Human, Theresa, Hwang, David, Illes, Judy, Jaffa, Matthew, James, Michael L, Janas, Anna, Johnson, Susan, Jones, Morgan, Jox, Ralf J, Kalanuria, Atul, Keller, Emanuela, Kennedy, Lori, Kennelly, Megan, Keogh, Maggie, Kim, Jenn, Kim, Keri, Kirsch, Hannah, Kirschen, Matthew, Ko, Nerissa, Kreitzer, Natalie, Kromm, Julie, Kumar, Abhay, Kurtz, Pedro, Laureys, Steven, Lejeune, Nicolas, Lewis, Ariane, Liang, John, Ling, Geoffrey, Livesay, Sarah, Luppi, Andrea, MacDonald, Jennifer, Maddux, Craig, Mahanes, Dea, Mainali, Shraddha, Maldonado, Nelson, Ribeiro, Rennan Martins, Mascia, Luciana, Massimini, Marcello, Mathur, Rohan, Mayer, Stephan, McCredie, Victoria, Mejia-Mantilla, Jorge, Mendoza, Michael, Menon, David, Meyfroidt, Geert, Mijangos, Julio, Moberg, Dick, Moheet, Asma, Montalenti, Elisa, Monti, Martin, Morrison, Chris, Munar, Marina, Murtaugh, Brooke, Naccache, Lionel, Nagayama, Masao, Nairon, Emerson, Nakagawa, Thomas, Naldi, Andrea, Narenthiran, Ganesalingam, Natarajan, Girija, Nemetsky, Esther, Newcombe, Virginia, Nielsen, Niklas, Niznick, Naomi, Noronha-Falcão, Filipa, Nyquist, Paul, Olson, DaiWai, Othman, Marwan, Owen, Adrian, Padayachy, Llewellyn, Pajoumand, Mehrnaz, Park, Soojin, Pergakis, Melissa, Perry, Heidi, Polizzotto, Len, Pouratian, Nader, Spivack, Marilyn Price, Prisco, Lara, Provencio, Javier, Puglises, Francesco, Puybasset, Louis, Rao, Chethan, Rasmussen, Lindsay, Rasulo, Frank, Ray, Bappaditya, Ricci, Zaccaria, Richardson, Risa, Shinotsuka, Cassia Righy, Robba, Chiara, Robertson, Courtney, Rohaut, Benjamin, Rolston, John, Romagnoli, Stefano, Rosanova, Mario, Rosenthal, Eric, Rowe, Shaun, Rubin, Michael, Russell, Mary Beth, Silva, Gisele Sampaio, Sanz, Leandro, Sarasso, Simone, Sarwal, Aarti, Schiff, Nicolas, Schnakers, Caroline, Seder, David, Shah, Vishank Arun, Shapiro-Rosenbaubm, Amy, Shapshak, Angela, Sharma, Kartavya, Sharma, Kumar Ajay, Shutter, Lori, Sitt, Jacobo, Slomine, Beth, Smetana, Keaton, Smielewski, Peter, Smith, Wade, Stamatakis, Emmanuel, Steinberg, Alexis, Stevens, Robert, Suarez, Jose, Sung, Gene, Sussman, Bethany, Taran, Shaurya, Mazzeo, Anna Teresa, Thibaut, Aurore, Thompson, David, Threlkeld, Zachary, Toker, Daniel, Torbey, Michel, Tosto, Jenna, Trevick, Stephen, Tsaousi, Georgia, Turgeon, Alexis, Udy, Andrew, Varelas, Panos, Vespa, Paul, Videtta, Walter, Voss, Henning, Vox, Ford, Wagner, Amy, Wahlster, Sarah, Wainwright, Mark, Whyte, John, Witherspoon, Briana, Yakhkind, Aleksandra (Sasha), Yeager, Susan, Young, Michael, Zafar, Sahar, Zafonte, Ross, Zahuranec, Darin, Zammit, Chris, Zhang, Bei, Ziai, Wendy, Zimmerman, Lara, and Zink, Elizabeth

Abstract

Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilit

Published
2024

12. Anomalous pressure effect on the magnetic ordering in multiferroic BiMnO3

Author

Chou, C. C., Taran, S., Her, J. L., Sun, C. P., Huang, C. L., Sakurai, H., Belik, A. A., Takayama-Muromachi, E., and Yang, H. D.

Subjects
Condensed Matter - Strongly Correlated Electrons
Abstract

We report the magnetic field dependent dc magnetization and the pressure-dependent (pmax ~ 16 kbar) ac susceptibilities Xp(T) on both powder and bulk multiferroic BiMnO3 samples, synthesized in different batches under high pressure. A clear ferromagnetic (FM) transition is observed at TC ~ 100 K, and increases with magnetic field. The magnetic hysteresis behavior is similar to that of a soft ferromagnet. Ac susceptibility data indicate that both the FM peak and its temperature (TC) decrease simultaneously with increasing pressure. Interestingly, above a certain pressure (9 ~ 11 kbar), another peak appears at Tp ~ 93 K, which also decreases with increasing pressure, with both these peaks persisting over some intermediate pressure range (9 ~ 13 kbar). The FM peak disappears with further application of pressure; however, the second peak survives until present pressure limit (pmax ~ 16 kbar). These features are considered to originate from the complex interplay of the magnetic and orbital structure of BiMnO3 being affected by pressure., Comment: 4 pages,4 figures, publised in Physical Review B 78, 092404/2008

Published
2010
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13. Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Hospital Course, Confounders, and Medications

Author

Barra, M, Zink, E, Bleck, T, Caceres, E, Farrokh, S, Foreman, B, Cediel, E, Hemphill, J, Nagayama, M, Olson, D, Suarez, J, Aiyagari, V, Akbari, Y, Al-Mufti, F, Alexander, S, Alexandrov, A, Alkhachroum, A, Amiri, M, Appavu, B, Gebre, M, Bader, M, Badjiata, N, Balu, R, Beekman, R, Beghi, E, Bell, K, Beqiri, E, Berlin, T, Bodien, Y, Boerwinkle, V, Boly, M, Bonnel, A, Brown, E, Carroll, E, Chou, S, Citerio, G, Classen, J, Condie, C, Cosmas, K, Creutzfeldt, C, Dangayach, N, Degeorgia, M, Der-Nigoghoss, C, Desai, M, Diringer, M, Dullaway, J, Edlow, B, Ercole, A, Estraneo, A, Falcone, G, Padayachy, L, Park, S, Pergakis, M, Polizzotto, L, Pouratian, N, Spivack, M, Prisco, L, Provencio, J, Puybasset, L, Rasmussen, L, Rass, V, Richardson, R, Shinots, C, Robba, C, Robertson, C, Rohaut, B, Rolston, J, Rosanova, M, Rosenthal, E, Russell, M, Silva, G, Sanz, L, Sarasso, S, Sarwal, A, Schiff, N, Schnakers, C, Seder, D, Shah, V, Shapiro-Rosen, A, Shapshak, A, Sharma, K, Sharshar, T, Shutter, L, Sitt, J, Slomine, B, Smielewski, P, Smith, W, Stamatakis, E, Steinberg, A, Ferioli, S, Fernandez-Esp, D, Fink, E, Fins, J, Frontera, J, Ganesan, R, Ghavam, A, Giacino, J, Gibbons, C, Gilmore, E, Gosseries, O, Green, T, Greer, D, Guanci, M, Hahn, C, Hakimi, R, Hanley, D, Hartings, J, Hassan, A, Hinson, H, Hirsch, K, Hocker, S, Hu, P, Hu, X, Human, T, Hwang, D, Illes, J, Jaffa, M, James, M, Janas, A, Jones, M, Keller, E, Keogh, M, Kim, J, Kim, K, Kirsch, H, Kirschen, M, Ko, N, Kondziella, D, Kreitzer, N, Stevens, R, Sussman, B, Taran, S, Thibaut, A, Threlkeld, Z, Tinti, L, Toker, D, Torbey, M, Trevick, S, Turgeon, A, Udy, A, Varelas, P, Venkatasubba, C, Vespa, P, Videtta, W, Voss, H, Vox, F, Wagner, A, Wainwright, M, Whyte, J, Witherspoon, B, Yakhind, A, Zafonte, R, Zahuranec, D, Zammit, C, Zhang, B, Ziai, W, Zimmerman, L, Kromm, J, Kumar, A, Kurtz, P, Laureys, S, Lawson, T, Lejeune, N, Lewis, A, Liang, J, Ling, G, Livesay, S, Luppi, A, Madden, L, Maddux, C, Mahanes, D, Mainali, S, Maldonado, N, Ribeiro, R, Massimini, M, Mayer, S, Mccredie, V, Mcnett, M, Mejia-Mantill, J, Menon, D, Meyfroidt, G, Mijangos, J, Moberg, D, Moheet, A, Molteni, E, Monti, M, Morrison, C, Muehlschlegel, S, Murtaugh, B, Naccache, L, Nairon, E, Natarajan, G, Newcombe, V, Nielsen, N, Noronha-Falc‹, F, Nyquist, P, Othman, M, Owen, A, Barra M. E., Zink E. K., Bleck T. P., Caceres E., Farrokh S., Foreman B., Cediel E. G., Hemphill J. C., Nagayama M., Olson D. W. M., Suarez J. I., Aiyagari V., Akbari Y., Al-Mufti F., Alexander S., Alexandrov A., Alkhachroum A., Amiri M., Appavu B., Gebre M. A., Bader M. K., Badjiata N., Balu R., Beekman R., Beghi E., Bell K., Beqiri E., Berlin T., Bodien Y., Boerwinkle V., Boly M., Bonnel A., Brown E., Carroll E., Chou S., Citerio G., Classen J., Condie C., Cosmas K., Creutzfeldt C., Dangayach N., DeGeorgia M., Der-Nigoghoss C., Desai M., Diringer M., Dullaway J., Edlow B., Ercole A., Estraneo A., Falcone G., Padayachy L., Park S., Pergakis M., Polizzotto L., Pouratian N., Spivack M. P., Prisco L., Provencio J., Puybasset L., Rasmussen L., Rass V., Richardson R., Shinots C. R., Robba C., Robertson C., Rohaut B., Rolston J., Rosanova M., Rosenthal E., Russell M. B., Silva G. S., Sanz L., Sarasso S., Sarwal A., Schiff N., Schnakers C., Seder D., Shah V. A., Shapiro-Rosen A., Shapshak A., Sharma K., Sharshar T., Shutter L., Sitt J., Slomine B., Smielewski P., Smith W., Stamatakis E., Steinberg A., Ferioli S., Fernandez-Esp D., Fink E., Fins J., Frontera J., Ganesan R., Ghavam A., Giacino J., Gibbons C., Gilmore E., Gosseries O., Green T., Greer D., Guanci M., Hahn C., Hakimi R., Hanley D. F., Hartings J., Hassan A., Hinson H., Hirsch K., Hocker S., Hu P., Hu X., Human T., Hwang D., Illes J., Jaffa M., James M. L., Janas A., Jones M., Keller E., Keogh M., Kim J., Kim K., Kirsch H., Kirschen M., Ko N., Kondziella D., Kreitzer N., Stevens R., Sussman B., Taran S., Thibaut A., Threlkeld Z., Tinti L., Toker D., Torbey M., Trevick S., Turgeon A., Udy A., Varelas P., Venkatasubba C., Vespa P., Videtta W., Voss H., Vox F., Wagner A., Wainwright M., Whyte J., Witherspoon B., Yakhind A., Zafonte R., Zahuranec D., Zammit C., Zhang B., Ziai W., Zimmerman L., Kromm J., Kumar A., Kurtz P., Laureys S., Lawson T., Lejeune N., Lewis A., Liang J., Ling G., Livesay S., Luppi A., Madden L., Maddux C., Mahanes D., Mainali S., Maldonado N., Ribeiro R. M., Massimini M., Mayer S., McCredie V., McNett M., Mejia-Mantill J., Menon D., Meyfroidt G., Mijangos J., Moberg D., Moheet A., Molteni E., Monti M., Morrison C., Muehlschlegel S., Murtaugh B., Naccache L., Nairon E., Natarajan G., Newcombe V., Nielsen N., Noronha-Falc‹ F., Nyquist P., Othman M., Owen A., Barra, M, Zink, E, Bleck, T, Caceres, E, Farrokh, S, Foreman, B, Cediel, E, Hemphill, J, Nagayama, M, Olson, D, Suarez, J, Aiyagari, V, Akbari, Y, Al-Mufti, F, Alexander, S, Alexandrov, A, Alkhachroum, A, Amiri, M, Appavu, B, Gebre, M, Bader, M, Badjiata, N, Balu, R, Beekman, R, Beghi, E, Bell, K, Beqiri, E, Berlin, T, Bodien, Y, Boerwinkle, V, Boly, M, Bonnel, A, Brown, E, Carroll, E, Chou, S, Citerio, G, Classen, J, Condie, C, Cosmas, K, Creutzfeldt, C, Dangayach, N, Degeorgia, M, Der-Nigoghoss, C, Desai, M, Diringer, M, Dullaway, J, Edlow, B, Ercole, A, Estraneo, A, Falcone, G, Padayachy, L, Park, S, Pergakis, M, Polizzotto, L, Pouratian, N, Spivack, M, Prisco, L, Provencio, J, Puybasset, L, Rasmussen, L, Rass, V, Richardson, R, Shinots, C, Robba, C, Robertson, C, Rohaut, B, Rolston, J, Rosanova, M, Rosenthal, E, Russell, M, Silva, G, Sanz, L, Sarasso, S, Sarwal, A, Schiff, N, Schnakers, C, Seder, D, Shah, V, Shapiro-Rosen, A, Shapshak, A, Sharma, K, Sharshar, T, Shutter, L, Sitt, J, Slomine, B, Smielewski, P, Smith, W, Stamatakis, E, Steinberg, A, Ferioli, S, Fernandez-Esp, D, Fink, E, Fins, J, Frontera, J, Ganesan, R, Ghavam, A, Giacino, J, Gibbons, C, Gilmore, E, Gosseries, O, Green, T, Greer, D, Guanci, M, Hahn, C, Hakimi, R, Hanley, D, Hartings, J, Hassan, A, Hinson, H, Hirsch, K, Hocker, S, Hu, P, Hu, X, Human, T, Hwang, D, Illes, J, Jaffa, M, James, M, Janas, A, Jones, M, Keller, E, Keogh, M, Kim, J, Kim, K, Kirsch, H, Kirschen, M, Ko, N, Kondziella, D, Kreitzer, N, Stevens, R, Sussman, B, Taran, S, Thibaut, A, Threlkeld, Z, Tinti, L, Toker, D, Torbey, M, Trevick, S, Turgeon, A, Udy, A, Varelas, P, Venkatasubba, C, Vespa, P, Videtta, W, Voss, H, Vox, F, Wagner, A, Wainwright, M, Whyte, J, Witherspoon, B, Yakhind, A, Zafonte, R, Zahuranec, D, Zammit, C, Zhang, B, Ziai, W, Zimmerman, L, Kromm, J, Kumar, A, Kurtz, P, Laureys, S, Lawson, T, Lejeune, N, Lewis, A, Liang, J, Ling, G, Livesay, S, Luppi, A, Madden, L, Maddux, C, Mahanes, D, Mainali, S, Maldonado, N, Ribeiro, R, Massimini, M, Mayer, S, Mccredie, V, Mcnett, M, Mejia-Mantill, J, Menon, D, Meyfroidt, G, Mijangos, J, Moberg, D, Moheet, A, Molteni, E, Monti, M, Morrison, C, Muehlschlegel, S, Murtaugh, B, Naccache, L, Nairon, E, Natarajan, G, Newcombe, V, Nielsen, N, Noronha-Falc‹, F, Nyquist, P, Othman, M, Owen, A, Barra M. E., Zink E. K., Bleck T. P., Caceres E., Farrokh S., Foreman B., Cediel E. G., Hemphill J. C., Nagayama M., Olson D. W. M., Suarez J. I., Aiyagari V., Akbari Y., Al-Mufti F., Alexander S., Alexandrov A., Alkhachroum A., Amiri M., Appavu B., Gebre M. A., Bader M. K., Badjiata N., Balu R., Beekman R., Beghi E., Bell K., Beqiri E., Berlin T., Bodien Y., Boerwinkle V., Boly M., Bonnel A., Brown E., Carroll E., Chou S., Citerio G., Classen J., Condie C., Cosmas K., Creutzfeldt C., Dangayach N., DeGeorgia M., Der-Nigoghoss C., Desai M., Diringer M., Dullaway J., Edlow B., Ercole A., Estraneo A., Falcone G., Padayachy L., Park S., Pergakis M., Polizzotto L., Pouratian N., Spivack M. P., Prisco L., Provencio J., Puybasset L., Rasmussen L., Rass V., Richardson R., Shinots C. R., Robba C., Robertson C., Rohaut B., Rolston J., Rosanova M., Rosenthal E., Russell M. B., Silva G. S., Sanz L., Sarasso S., Sarwal A., Schiff N., Schnakers C., Seder D., Shah V. A., Shapiro-Rosen A., Shapshak A., Sharma K., Sharshar T., Shutter L., Sitt J., Slomine B., Smielewski P., Smith W., Stamatakis E., Steinberg A., Ferioli S., Fernandez-Esp D., Fink E., Fins J., Frontera J., Ganesan R., Ghavam A., Giacino J., Gibbons C., Gilmore E., Gosseries O., Green T., Greer D., Guanci M., Hahn C., Hakimi R., Hanley D. F., Hartings J., Hassan A., Hinson H., Hirsch K., Hocker S., Hu P., Hu X., Human T., Hwang D., Illes J., Jaffa M., James M. L., Janas A., Jones M., Keller E., Keogh M., Kim J., Kim K., Kirsch H., Kirschen M., Ko N., Kondziella D., Kreitzer N., Stevens R., Sussman B., Taran S., Thibaut A., Threlkeld Z., Tinti L., Toker D., Torbey M., Trevick S., Turgeon A., Udy A., Varelas P., Venkatasubba C., Vespa P., Videtta W., Voss H., Vox F., Wagner A., Wainwright M., Whyte J., Witherspoon B., Yakhind A., Zafonte R., Zahuranec D., Zammit C., Zhang B., Ziai W., Zimmerman L., Kromm J., Kumar A., Kurtz P., Laureys S., Lawson T., Lejeune N., Lewis A., Liang J., Ling G., Livesay S., Luppi A., Madden L., Maddux C., Mahanes D., Mainali S., Maldonado N., Ribeiro R. M., Massimini M., Mayer S., McCredie V., McNett M., Mejia-Mantill J., Menon D., Meyfroidt G., Mijangos J., Moberg D., Moheet A., Molteni E., Monti M., Morrison C., Muehlschlegel S., Murtaugh B., Naccache L., Nairon E., Natarajan G., Newcombe V., Nielsen N., Noronha-Falc‹ F., Nyquist P., Othman M., and Owen A.

Abstract

The convergence of an interdisciplinary team of neurocritical care specialists to organize the Curing Coma Campaign is the first effort of its kind to coordinate national and international research efforts aimed at a deeper understanding of disorders of consciousness (DoC). This process of understanding includes translational research from bench to bedside, descriptions of systems of care delivery, diagnosis, treatment, rehabilitation, and ethical frameworks. The description and measurement of varying confounding factors related to hospital care was thought to be critical in furthering meaningful research in patients with DoC. Interdisciplinary hospital care is inherently varied across geographical areas as well as community and academic medical centers. Access to monitoring technologies, specialist consultation (medical, nursing, pharmacy, respiratory, and rehabilitation), staffing resources, specialty intensive and acute care units, specialty medications and specific surgical, diagnostic and interventional procedures, and imaging is variable, and the impact on patient outcome in terms of DoC is largely unknown. The heterogeneity of causes in DoC is the source of some expected variability in care and treatment of patients, which necessitated the development of a common nomenclature and set of data elements for meaningful measurement across studies. Guideline adherence in hemorrhagic stroke and severe traumatic brain injury may also be variable due to moderate or low levels of evidence for many recommendations. This article outlines the process of the development of common data elements for hospital course, confounders, and medications to streamline definitions and variables to collect for clinical studies of DoC.

Published
2023

14. Utilization of mechanical power and associations with clinical outcomes in brain injured patients: a secondary analysis of the extubation strategies in neuro-intensive care unit patients and associations with outcome (ENIO) trial

Author

Wahlster, S, Sharma, M, Taran, S, Town, J, Stevens, R, Cinotti, R, Asehoune, K, Pelosi, P, Robba, C, Abback, P, Codorniu, A, Citerio, G, Sala, V, Astuto, M, Tringali, E, Alampi, D, Rocco, M, Maugeri, J, Bellissima, A, Filippini, M, Lazzeri, N, Cortegiani, A, Ippolito, M, Battaglini, D, Biston, P, Al-Gharyani, M, Chabanne, R, Astier, L, Soyer, B, Gaugain, S, Zimmerli, A, Pietsch, U, Filipovic, M, Brandi, G, Bicciato, G, Serrano, A, Monleon, B, van Vliet, P, Gerretsen, B, Ortiz-Macias, I, Oto, J, Enomoto, N, Matsuda, T, Masui, N, Garcon, P, Zarka, J, Vermeijden, W, Cornet, A, Inurrigarro, S, Dominguez, R, Bellini, M, Gomez Haedo, M, Lamot, L, Orquera, J, Biais, M, Georges, D, Baronia, A, Miranda-Ackerman, R, Barbosa-Camacho, F, Porter, J, Lopez-Morales, M, Geeraerts, T, Compagnon, B, Perez-Torres, D, Prol-Silva, E, Yahya, H, Khaled, A, Ghula, M, Andrea, C, Daniela, P, Deana, C, Vetrugno, L, Chavez, M, Trujillo, R, Legros, V, Brochet, B, Huet, O, Geslain, M, van der Jagt, M, van Steenkiste, J, Ahmed, H, Coombs, A, Welbourne, J, Velarde Pineda, A, Nubert Castillo, V, Azab, M, Azzam, A, van Meenen, D, Gasca, G, Arellano, A, Galicia-Espinosa, F, Garcia-Ramos, J, Yadav, G, Jha, A, Robert-Edan, V, Rodie-Talbere, P, Jain, G, Panda, S, Agarwal, S, Deewan, Y, Reza, S, Hossain, M, Papadas, C, Chantziara, V, Sklavou, C, Hourmant, Y, Grillot, N, Pirracchio, R, Akkari, A, Abdelaty, M, Hashim, A, Launey, Y, Masseret, E, Lasocki, S, Gergaud, S, Mouclier, N, Saxena, S, Agrawal, A, Mishra, S, Samal, S, Mijangos, J, Haenggi, M, Gurjar, M, Schultz, M, Kaye, C, Godoy, D, Alvarez, P, Ioakeimidou, A, Ueno, Y, Badenes, R, Suei Elbuzidi, A, Piagnerelli, M, Elhadi, M, Digitale, J, Fong, N, Cerda, R, de la Torre Peredo, N, Wahlster S., Sharma M., Taran S., Town J. A., Stevens R. D., Cinotti R., Asehoune K., Pelosi P., Robba C., Abback P. -S., Codorniu A., Citerio G., Sala V. L., Astuto M., Tringali E., Alampi D., Rocco M., Maugeri J. G., Bellissima A., Filippini M., Lazzeri N., Cortegiani A., Ippolito M., Battaglini D., Biston P., Al-Gharyani M. F., Chabanne R., Astier L., Soyer B., Gaugain S., Zimmerli A., Pietsch U., Filipovic M., Brandi G., Bicciato G., Serrano A., Monleon B., van Vliet P., Gerretsen B. M., Ortiz-Macias I. X., Oto J., Enomoto N., Matsuda T., Masui N., Garcon P., Zarka J., Vermeijden W. J., Cornet A. D., Inurrigarro S. R., Dominguez R. C. L., Bellini M. M., Gomez Haedo M. M., Lamot L., Orquera J., Biais M., Georges D., Baronia A., Miranda-Ackerman R. C., Barbosa-Camacho F. J., Porter J., Lopez-Morales M., Geeraerts T., Compagnon B., Perez-Torres D., Prol-Silva E., Yahya H. B., Khaled A., Ghula M., Andrea C. N., Daniela P. M., Deana C., Vetrugno L., Chavez M. J. R., Trujillo R. M., Legros V., Brochet B., Huet O., Geslain M., van der Jagt M., van Steenkiste J., Ahmed H., Coombs A. E., Welbourne J., Velarde Pineda A. A., Nubert Castillo V. H., Azab M. A., Azzam A. Y., van Meenen D. M. P., Gasca G. A., Arellano A., Galicia-Espinosa F., Garcia-Ramos J. C., Yadav G., Jha A. K., Robert-Edan V., Rodie-Talbere P. -A., Jain G., Panda S., Agarwal S., Deewan Y., Reza S. T., Hossain M. M., Papadas C., Chantziara V., Sklavou C., Hourmant Y., Grillot N., Pirracchio R., Akkari A., Abdelaty M., Hashim A., Launey Y., Masseret E., Lasocki S., Gergaud S., Mouclier N., Saxena S., Agrawal A., Mishra S. B., Samal S., Mijangos J. C., Haenggi M., Gurjar M., Schultz M. J., Kaye C., Godoy D. A., Alvarez P., Ioakeimidou A., Ueno Y., Badenes R., Suei Elbuzidi A. A., Piagnerelli M., Elhadi M., Digitale J. C., Fong N., Cerda R. C., de la Torre Peredo N., Wahlster, S, Sharma, M, Taran, S, Town, J, Stevens, R, Cinotti, R, Asehoune, K, Pelosi, P, Robba, C, Abback, P, Codorniu, A, Citerio, G, Sala, V, Astuto, M, Tringali, E, Alampi, D, Rocco, M, Maugeri, J, Bellissima, A, Filippini, M, Lazzeri, N, Cortegiani, A, Ippolito, M, Battaglini, D, Biston, P, Al-Gharyani, M, Chabanne, R, Astier, L, Soyer, B, Gaugain, S, Zimmerli, A, Pietsch, U, Filipovic, M, Brandi, G, Bicciato, G, Serrano, A, Monleon, B, van Vliet, P, Gerretsen, B, Ortiz-Macias, I, Oto, J, Enomoto, N, Matsuda, T, Masui, N, Garcon, P, Zarka, J, Vermeijden, W, Cornet, A, Inurrigarro, S, Dominguez, R, Bellini, M, Gomez Haedo, M, Lamot, L, Orquera, J, Biais, M, Georges, D, Baronia, A, Miranda-Ackerman, R, Barbosa-Camacho, F, Porter, J, Lopez-Morales, M, Geeraerts, T, Compagnon, B, Perez-Torres, D, Prol-Silva, E, Yahya, H, Khaled, A, Ghula, M, Andrea, C, Daniela, P, Deana, C, Vetrugno, L, Chavez, M, Trujillo, R, Legros, V, Brochet, B, Huet, O, Geslain, M, van der Jagt, M, van Steenkiste, J, Ahmed, H, Coombs, A, Welbourne, J, Velarde Pineda, A, Nubert Castillo, V, Azab, M, Azzam, A, van Meenen, D, Gasca, G, Arellano, A, Galicia-Espinosa, F, Garcia-Ramos, J, Yadav, G, Jha, A, Robert-Edan, V, Rodie-Talbere, P, Jain, G, Panda, S, Agarwal, S, Deewan, Y, Reza, S, Hossain, M, Papadas, C, Chantziara, V, Sklavou, C, Hourmant, Y, Grillot, N, Pirracchio, R, Akkari, A, Abdelaty, M, Hashim, A, Launey, Y, Masseret, E, Lasocki, S, Gergaud, S, Mouclier, N, Saxena, S, Agrawal, A, Mishra, S, Samal, S, Mijangos, J, Haenggi, M, Gurjar, M, Schultz, M, Kaye, C, Godoy, D, Alvarez, P, Ioakeimidou, A, Ueno, Y, Badenes, R, Suei Elbuzidi, A, Piagnerelli, M, Elhadi, M, Digitale, J, Fong, N, Cerda, R, de la Torre Peredo, N, Wahlster S., Sharma M., Taran S., Town J. A., Stevens R. D., Cinotti R., Asehoune K., Pelosi P., Robba C., Abback P. -S., Codorniu A., Citerio G., Sala V. L., Astuto M., Tringali E., Alampi D., Rocco M., Maugeri J. G., Bellissima A., Filippini M., Lazzeri N., Cortegiani A., Ippolito M., Battaglini D., Biston P., Al-Gharyani M. F., Chabanne R., Astier L., Soyer B., Gaugain S., Zimmerli A., Pietsch U., Filipovic M., Brandi G., Bicciato G., Serrano A., Monleon B., van Vliet P., Gerretsen B. M., Ortiz-Macias I. X., Oto J., Enomoto N., Matsuda T., Masui N., Garcon P., Zarka J., Vermeijden W. J., Cornet A. D., Inurrigarro S. R., Dominguez R. C. L., Bellini M. M., Gomez Haedo M. M., Lamot L., Orquera J., Biais M., Georges D., Baronia A., Miranda-Ackerman R. C., Barbosa-Camacho F. J., Porter J., Lopez-Morales M., Geeraerts T., Compagnon B., Perez-Torres D., Prol-Silva E., Yahya H. B., Khaled A., Ghula M., Andrea C. N., Daniela P. M., Deana C., Vetrugno L., Chavez M. J. R., Trujillo R. M., Legros V., Brochet B., Huet O., Geslain M., van der Jagt M., van Steenkiste J., Ahmed H., Coombs A. E., Welbourne J., Velarde Pineda A. A., Nubert Castillo V. H., Azab M. A., Azzam A. Y., van Meenen D. M. P., Gasca G. A., Arellano A., Galicia-Espinosa F., Garcia-Ramos J. C., Yadav G., Jha A. K., Robert-Edan V., Rodie-Talbere P. -A., Jain G., Panda S., Agarwal S., Deewan Y., Reza S. T., Hossain M. M., Papadas C., Chantziara V., Sklavou C., Hourmant Y., Grillot N., Pirracchio R., Akkari A., Abdelaty M., Hashim A., Launey Y., Masseret E., Lasocki S., Gergaud S., Mouclier N., Saxena S., Agrawal A., Mishra S. B., Samal S., Mijangos J. C., Haenggi M., Gurjar M., Schultz M. J., Kaye C., Godoy D. A., Alvarez P., Ioakeimidou A., Ueno Y., Badenes R., Suei Elbuzidi A. A., Piagnerelli M., Elhadi M., Digitale J. C., Fong N., Cerda R. C., and de la Torre Peredo N.

Abstract

Background: There is insufficient evidence to guide ventilatory targets in acute brain injury (ABI). Recent studies have shown associations between mechanical power (MP) and mortality in critical care populations. We aimed to describe MP in ventilated patients with ABI, and evaluate associations between MP and clinical outcomes. Methods: In this preplanned, secondary analysis of a prospective, multi-center, observational cohort study (ENIO, NCT03400904), we included adult patients with ABI (Glasgow Coma Scale ≤ 12 before intubation) who required mechanical ventilation (MV) ≥ 24 h. Using multivariable log binomial regressions, we separately assessed associations between MP on hospital day (HD)1, HD3, HD7 and clinical outcomes: hospital mortality, need for reintubation, tracheostomy placement, and development of acute respiratory distress syndrome (ARDS). Results: We included 1217 patients (mean age 51.2 years [SD 18.1], 66% male, mean body mass index [BMI] 26.3 [SD 5.18]) hospitalized at 62 intensive care units in 18 countries. Hospital mortality was 11% (n = 139), 44% (n = 536) were extubated by HD7 of which 20% (107/536) required reintubation, 28% (n = 340) underwent tracheostomy placement, and 9% (n = 114) developed ARDS. The median MP on HD1, HD3, and HD7 was 11.9 J/min [IQR 9.2–15.1], 13 J/min [IQR 10–17], and 14 J/min [IQR 11–20], respectively. MP was overall higher in patients with ARDS, especially those with higher ARDS severity. After controlling for same-day pressure of arterial oxygen/fraction of inspired oxygen (P/F ratio), BMI, and neurological severity, MP at HD1, HD3, and HD7 was independently associated with hospital mortality, reintubation and tracheostomy placement. The adjusted relative risk (aRR) was greater at higher MP, and strongest for: mortality on HD1 (compared to the HD1 median MP 11.9 J/min, aRR at 17 J/min was 1.22, 95% CI 1.14–1.30) and HD3 (1.38, 95% CI 1.23–1.53), reintubation on HD1 (1.64; 95% CI 1.57–1.72), and tracheostomy on HD7 (1

Published
2023

21. Polypharmacology-based kinome screen identifies new regulators of KSHV reactivation

Author

Annabel T. Olson, Yuqi Kang, Anushka M. Ladha, Chuan Bian Lim, Michael Lagunoff, Taran S. Gujral, and Adam P. Geballe

Subjects
Article
Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi’s sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically neu), ERBB3 (HER3), ERBB4 (HER4), MKNK2 (MNK2), ITK, TEC, and DSTYK (RIPK5). Conversely, ERBB1 (EGFR1 or HER1), MKNK1 (MNK1) and FRK (PTK5) were found to promote the maintenance of latency. Mechanistic characterization of ERBB2 pro-lytic functions revealed a signaling connection between ERBB2 and the activation of CREB1, a transcription factor that drives KSHV lytic gene expression. These studies provided a proof-of-principle application of a polypharmacology-based kinome screen for the study of KSHV reactivation and enabled the discovery of both kinase inhibitors and specific kinases that regulate the KSHV latent-to-lytic replication switch.Author SummaryKaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma, a cancer particularly prevalent in Africa. In cancer cells, the virus persists in a quiescent form called latency, in which only a few viral genes are made. Periodically, the virus switches into an active replicative cycle in which most of the viral genes are made and new virus is produced. What controls the switch from latency to active replication is not well understood, but cellular kinases, enzymes that control many cellular processes, have been implicated. Using a cell culture model of KSHV reactivation along with an innovative screening method that probes the effects of many cellular kinases simultaneously, we identified drugs that significantly limit KSHV reactivation, as well as specific kinases that either enhance or restrict KSHV replicative cycle. Among these were the ERBB kinases which are known to regulate growth of cancer cells. Understanding how these and other kinases contribute to the switch leading to production of more infectious virus helps us understand the mediators and mechanisms of KSHV diseases. Additionally, because kinase inhibitors are proving to be effective for treating other diseases including some cancers, identifying ones that restrict KSHV replicative cycle may lead to new approaches to treating KSHV-related diseases.

Published
2023

28. Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway

Author

Patel, Seema R., primary, Lundgren, Taran S., additional, Baldwin, Wallace Hunter, additional, Cox, Courtney, additional, Parker, Ernest T., additional, Healey, John F., additional, Jajosky, Ryan P., additional, Zerra, Patricia E., additional, Josephson, Cassandra D., additional, Doering, Christopher B., additional, Stowell, Sean R., additional, and Meeks, Shannon L., additional

Published
2022
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32. Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice

Author

Taran S. Lundgren, Gabriela Denning, Sean R. Stowell, H. Trent Spencer, and Christopher B. Doering

Subjects
Mice, Factor VIII, Animals, Hematology, Genetic Therapy, Transgenes, Hemophilia A, Hemostatics
Abstract

Advances in the development of novel treatment options for hemophilia A are prevalent. However, the anti–factor VIII (FVIII) neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. Although some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of 4 adeno-associated viral (AAV) vector candidates encoding 2 different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that (1) identifies initial AAV-FVIII product expression kinetics as the dominant risk factor for inhibitor development, (2) predicts a therapeutic window where immune tolerance is achieved, and (3) demonstrates evidence of gene therapy–based immune tolerance induction. Although there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines.

Published
2021

36. Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII

Author

Russell, Athena L., primary, Prince, Chengyu, additional, Lundgren, Taran S., additional, Knight, Kristopher A., additional, Denning, Gabriela, additional, Alexander, Jordan S., additional, Zoine, Jaquelyn T., additional, Spencer, H. Trent, additional, Chandrakasan, Shanmuganathan, additional, and Doering, Christopher B., additional

Published
2021
Full Text
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