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5. Preface

Author

Barnett, Christopher B.

Published
2014

9. Contents

Author

Barnett, Christopher B.

Published
2014

14. Back Cover

Author

Barnett, Christopher B.

Published
2014

16. Works Cited

Author

Barnett, Christopher B.

Published
2014

18. Prognostic significance of haemodynamic parameters in patients with cardiogenic shock.

Author

Berg, David, Kaur, Gurleen, Bohula, Erin, Baird-Zars, Vivian, Alviar, Carlos, Barnett, Christopher, Barsness, Gregory, Burke, James, Chaudhry, Sunit-Preet, Chonde, Meshe, Cooper, Howard, Daniels, Lori, Dodson, Mark, Gerber, Daniel, Ghafghazi, Shahab, Gidwani, Umesh, Goldfarb, Michael, Guo, Jianping, Hillerson, Dustin, Kenigsberg, Benjamin, Kochar, Ajar, Kontos, Michael, Kwon, Younghoon, Lopes, Mathew, Loriaux, Daniel, Miller, P, Papolos, Alexander, Patel, Siddharth, Pisani, Barbara, Potter, Brian, Prasad, Rajnish, Rowsell, Robert, Shah, Kevin, Sinha, Shashank, Smith, Timothy, Solomon, Michael, Teuteberg, Jeffrey, Thompson, Andrea, Zakaria, Sammy, Katz, Jason, van Diepen, Sean, Morrow, David, and OBrien, Connor

Subjects
Cardiogenic shock, Haemodynamics, Outcomes, Pulmonary artery catheter, Humans, Shock, Cardiogenic, Prognosis, Hemodynamics, Vascular Resistance, Lactates
Abstract

AIMS: Invasive haemodynamic assessment with a pulmonary artery catheter is often used to guide the management of patients with cardiogenic shock (CS) and may provide important prognostic information. We aimed to assess prognostic associations and relationships to end-organ dysfunction of presenting haemodynamic parameters in CS. METHODS AND RESULTS: The Critical Care Cardiology Trials Network is an investigator-initiated multicenter registry of cardiac intensive care units (CICUs) in North America coordinated by the TIMI Study Group. Patients with CS (2018-2022) who underwent invasive haemodynamic assessment within 24 h of CICU admission were included. Associations of haemodynamic parameters with in-hospital mortality were assessed using logistic regression, and associations with presenting serum lactate were assessed using least squares means regression. Sensitivity analyses were performed excluding patients on temporary mechanical circulatory support and adjusted for vasoactive-inotropic score. Among the 3603 admissions with CS, 1473 had haemodynamic data collected within 24 h of CICU admission. The median cardiac index was 1.9 (25th-75th percentile, 1.6-2.4) L/min/m2 and mean arterial pressure (MAP) was 74 (66-86) mmHg. Parameters associated with mortality included low MAP, low systolic blood pressure, low systemic vascular resistance, elevated right atrial pressure (RAP), elevated RAP/pulmonary capillary wedge pressure ratio, and low pulmonary artery pulsatility index. These associations were generally consistent when controlling for the intensity of background pharmacologic and mechanical haemodynamic support. These parameters were also associated with higher presenting serum lactate. CONCLUSION: In a contemporary CS population, presenting haemodynamic parameters reflecting decreased systemic arterial tone and right ventricular dysfunction are associated with adverse outcomes and systemic hypoperfusion.

Published
2023

19. The management of heart failure cardiogenic shock: an international RAND appropriateness panel

Author

Williams, Stefan, Kalakoutas, Antonis, Olusanya, Segun, Schrage, Benedict, Tavazzi, Guido, Carnicelli, Anthony P., Montero, Santiago, Vandenbriele, Christophe, Luk, Adriana, Lim, Hoong Sern, Bhagra, Sai, Ott, Sascha C., Farrero, Marta, Samsky, Marc D., Kennedy, Jamie L. W., Sen, Sounok, Agrawal, Richa, Rampersad, Penelope, Coniglio, Amanda, Pappalardo, Federico, Barnett, Christopher, and Proudfoot, Alastair G.

Published
2024
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21. Pulmonary Artery Catheter Use and Mortality in the Cardiac Intensive Care Unit.

Author

Kadosh, Bernard, Berg, David, Bohula, Erin, Park, Jeong-Gun, Baird-Zars, Vivian, Alviar, Carlos, Alzate, James, Barnett, Christopher, Barsness, Gregory, Burke, James, Chaudhry, Sunit-Preet, Daniels, Lori, DeFilippis, Andrew, Delicce, Anthony, Fordyce, Christopher, Ghafghazi, Shahab, Gidwani, Umesh, Goldfarb, Michael, Katz, Jason, Keeley, Ellen, Kenigsberg, Benjamin, Kontos, Michael, Lawler, Patrick, Leibner, Evan, Menon, Venu, Metkus, Thomas, Miller, P, OBrien, Connor, Papolos, Alexander, Prasad, Rajnish, Shah, Kevin, Sinha, Shashank, Snell, R, So, Derek, Solomon, Michael, Ternus, Bradley, Teuteberg, Jeffrey, Toole, Joseph, van Diepen, Sean, Morrow, David, and Roswell, Robert

Subjects
cardiac intensive care, pulmonary artery catheter, shock, Humans, Pulmonary Artery, Heart Failure, Intensive Care Units, Hospitalization, Hospital Mortality, Catheters
Abstract

BACKGROUND: The appropriate use of pulmonary artery catheters (PACs) in critically ill cardiac patients remains debated. OBJECTIVES: The authors aimed to characterize the current use of PACs in cardiac intensive care units (CICUs) with attention to patient-level and institutional factors influencing their application and explore the association with in-hospital mortality. METHODS: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America. Between 2017 and 2021, participating centers contributed annual 2-month snapshots of consecutive CICU admissions. Admission diagnoses, clinical and demographic data, use of PACs, and in-hospital mortality were captured. RESULTS: Among 13,618 admissions at 34 sites, 3,827 were diagnosed with shock, with 2,583 of cardiogenic etiology. The use of mechanical circulatory support and heart failure were the patient-level factors most strongly associated with a greater likelihood of the use of a PAC (OR: 5.99 [95% CI: 5.15-6.98]; P < 0.001 and OR: 3.33 [95% CI: 2.91-3.81]; P

Published
2023

22. Clinical and biological heterogeneity of multisystem inflammatory syndrome in adults following SARS-CoV-2 infection: a case series

Author

Barth, Kaia E, Spottiswoode, Natasha, Hurabielle, Charlotte, Subbaraj, Lakshmi, Consortium, COMET, Calfee, Carolyn S, Matthay, Michael A, French, Sarah, Connolly, Andrew, Hewitt, Stephen M, Vannella, Kevin M, Barnett, Christopher, Langelier, Charles R, and Patterson, Sarah

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Coronaviruses Disparities and At-Risk Populations, Infectious Diseases, Coronaviruses, Prevention, Autoimmune Disease, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Inflammatory and immune system, Infection, Good Health and Well Being, COVID-19, MIS-A, myocarditis, SARS-CoV-2, multisystem inflammatory syndrome, DKA, COMET Consortium, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceMultisystem inflammatory syndrome in adults (MIS-A) is a poorly understood complication of SARS-CoV-2 infection with significant morbidity and mortality.ObjectiveIdentify clinical, immunological, and histopathologic features of MIS-A to improve understanding of the pathophysiology and approach to treatment.DesignThree cases of MIS-A following SARS-CoV-2 infection were clinically identified between October 2021 - March 2022 using the U.S. Centers for Disease Control and Prevention diagnostic criteria. Clinical, laboratory, imaging, and tissue data were assessed.FindingsAll three patients developed acute onset cardiogenic shock and demonstrated elevated inflammatory biomarkers at the time of hospital admission that resolved over time. One case co-occurred with new onset Type 1 diabetes and sepsis. Retrospective analysis of myocardial tissue from one case identified SARS-CoV-2 RNA. All three patients fully recovered with standard of care interventions plus immunomodulatory therapy that included intravenous immunoglobulin, corticosteroids, and in two cases, anakinra.ConclusionMIS-A is a severe post-acute sequela of COVID-19 characterized by systemic elevation of inflammatory biomarkers. In this series of three cases, we find that although clinical courses and co-existent diseases vary, even severe presentations have potential for full recovery with prompt recognition and treatment. In addition to cardiogenic shock, glucose intolerance, unmasking of autoimmune disease, and sepsis can be features of MIS-A, and SARS-CoV-2 myocarditis can lead to a similar clinical syndrome.

Published
2023

23. Critical Care Cardiology Trials Network (CCCTN): a cohort profile.

Author

Metkus, Thomas, Baird-Zars, Vivian, Alfonso, Carlos, Alviar, Carlos, Barnett, Christopher, Barsness, Gregory, Berg, David, Bertic, Mia, Bohula, Erin, Burke, James, Burstein, Barry, Chaudhry, Sunit-Preet, Cooper, Howard, Daniels, Lori, Fordyce, Christopher, Ghafghazi, Shahab, Goldfarb, Michael, Katz, Jason, Keeley, Ellen, Keller, Norma, Kenigsberg, Benjamin, Kontos, Michael, Kwon, Younghoon, Lawler, Patrick, Leibner, Evan, Liu, Shuangbo, Menon, Venu, Miller, P, Newby, L, Papolos, Alexander, Pierce, Matthew, Prasad, Rajnish, Pisani, Barbara, Potter, Brian, Roswell, Robert, Sinha, Shashank, Shah, Kevin, Smith, Timothy, Snell, R, So, Derek, Solomon, Michael, Ternus, Bradley, Teuteberg, Jeffrey, van Diepen, Sean, Zakaria, Sammy, Morrow, David, and OBrien, Connor

Subjects
Cardiac ICU, Cohort, Critical care, Epidemiology, Humans, United States, Critical Illness, Coronary Care Units, Critical Care, Registries, Cardiology
Abstract

AIMS: The aims of the Critical Care Cardiology Trials Network (CCCTN) are to develop a registry to investigate the epidemiology of cardiac critical illness and to establish a multicentre research network to conduct randomised clinical trials (RCTs) in patients with cardiac critical illness. METHODS AND RESULTS: The CCCTN was founded in 2017 with 16 centres and has grown to a research network of over 40 academic and clinical centres in the United States and Canada. Each centre enters data for consecutive cardiac intensive care unit (CICU) admissions for at least 2 months of each calendar year. More than 20 000 unique CICU admissions are now included in the CCCTN Registry. To date, scientific observations from the CCCTN Registry include description of variations in care, the epidemiology and outcomes of all CICU patients, as well as subsets of patients with specific disease states, such as shock, heart failure, renal dysfunction, and respiratory failure. The CCCTN has also characterised utilization patterns, including use of mechanical circulatory support in response to changes in the heart transplantation allocation system, and the use and impact of multidisciplinary shock teams. Over years of multicentre collaboration, the CCCTN has established a robust research network to facilitate multicentre registry-based randomised trials in patients with cardiac critical illness. CONCLUSION: The CCCTN is a large, prospective registry dedicated to describing processes-of-care and expanding clinical knowledge in cardiac critical illness. The CCCTN will serve as an investigational platform from which to conduct randomised controlled trials in this important patient population.

Published
2022

24. Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.

Author

Qian, Xuyu, DeGennaro, Ellen, Talukdar, Maya, Akula, Shyam, Lai, Abbe, Shao, Diane, Gonzalez, Dilenny, Marciano, Jack, Smith, Richard, Hylton, Norma, Yang, Edward, Bazan, J, Barrett, Lee, Yeh, Rebecca, Hill, R, Beck, Samantha, Otani, Aoi, Angad, Jolly, Mitani, Tadahiro, Posey, Jennifer, Pehlivan, Davut, Calame, Daniel, Aydin, Hatip, Yesilbas, Osman, Parks, Kendall, England, Eleina, Im, Kiho, Taranath, Ajay, Scott, Hamish, Barnett, Christopher, Arts, Peer, Sherr, Elliott, Lupski, James, Walsh, Christopher, and Argilli, Emanuela

Subjects
apoptosis, cerebral cortex, congenital brain malformation, corpus callosum, development, genetics, kinesin, migration, organoid, Humans, Animals, Mice, Kinesins, Neurons, Focal Adhesion Protein-Tyrosine Kinases, Apoptosis, Brain
Abstract

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

Published
2022

25. Contemporary Training in American Critical Care Cardiology: Minnesota Critical Care Cardiology Education Summit: JACC Scientific Expert Panel

Author

Elliott, Andrea M., Bartos, Jason A., Barnett, Christopher F., Miller, P. Elliott, Roswell, Robert O., Alviar, Carlos, Bennett, Courtney, Berg, David D., Bohula, Erin A., Chonde, Meshe, Dahiya, Garima, Fleitman, Jessica, Gage, Ann, Hansra, Barinder S., Higgins, Andrew, Hollenberg, Steven M., Horowitz, James M., Jentzer, Jacob C., Katz, Jason N., Karpenshif, Yoav, Lee, Ran, Menon, Venu, Metkus, Thomas S., Mukundan, Srini, Rhinehart, Zachary J., Senman, Balimkiz, Senussi, Mourad, Solomon, Michael A., Vallabhajosyula, Saraschandra, and Dudzinski, David M.

Published
2024
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26. Current practices in the management of temporary mechanical circulatory support: A survey of CICU directors in North America

Author

Balgobind, Amrita, Pierce, Matthew, Alviar, Carlos, Barnett, Christopher, Barsness, Gregory, Chaudhry, Sunit-preet, Chonde, Meshe, Cooper, Howard, Daniels, Lori, Gidwani, Umesh, Fordyce, Christopher, Goldfarb, Michael, Katz, Jason N., Kontos, Michael, Kwon, Younghoon, Liebner, Evan, Liu, Shuangbo, Miller, P. Elliott, Newby, L.K., O'Brien, Connor, Papolos, Alexander, Pisani, Barbara, Potter, Brian, Proudfoot, Alastair, Roswell, Robert O., Sinha, Shashank S., Smith, Timothy D., Thompson, Andrea D., van Diepen, Sean, Zakaria, Sammy, Morrow, David, and Villela, Miguel Alvarez

Published
2024
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28. Continuum of Preshock to Classic Cardiogenic Shock in the Critical Care Cardiology Trials Network Registry

Author

Patel, Siddharth M., Berg, David D., Bohula, Erin A., Baird-Zars, Vivian M., Park, Jeong-Gun, Barnett, Christopher F., Daniels, Lori B., Fordyce, Christopher B., Ghafghazi, Shahab, Goldfarb, Michael J., Gorder, Kari, Kwon, Younghoon, Leibner, Evan, Menon, Venu, Potter, Brian J., Prasad, Rajnish, Solomon, Michael A., Teuteberg, Jeffrey J., Thompson, Andrea D., Zakaria, Sammy, Katz, Jason N., van Diepen, Sean, and Morrow, David A.

Published
2024
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29. RNA variant assessment using transactivation and transdifferentiation

Author

Azmanov, Dimitar N., Barnett, Christopher P., Barry, Simon C., Baynam, Gareth, Berkovic, Samuel F., Christodoulou, John, Coman, David J., Cooper, Sandra, Corbett, Mark A., Delatycki, Martin, Dudding, Tracy E., Fletcher, Sue, Gardner, Alison E., Gecz, Jozef, Higgins, Megan J., Hildebrand, Michael S., Jolly, Lachlan A., Lister, Ryan, McGaughran, Julie, Pflueger, Christian, Poulton, Cathryn, Roscioli, Tony, Hamish S. Scott, Ingrid Scheffer, Sinclair, Andrew H., Spurdle, Amanda B., Tan, Tiong Y., van Eyk, Clare L., Voineagu, Irina, Nicolas-Martinez, Emmylou C., Robinson, Olivia, Gardner, Alison, Ritchie, Tarin, Kroes, Thessa, Scheffer, Ingrid E., Barnier, Jean-Vianney, Rousseau, Véronique, Genevieve, David, Haushalter, Virginie, Piton, Amélie, Denommé-Pichon, Anne-Sophie, Bruel, Ange-Line, Nambot, Sophie, Isidor, Bertrand, Grigg, John, Gonzalez, Tina, Ghedia, Sondhya, Marchant, Rhett G., Bournazos, Adam, Wong, Wui-Kwan, Webster, Richard I., Evesson, Frances J., Jones, Kristi J., and Cooper, Sandra T.

Published
2024
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30. Meaningful coproduction with clinicians: establishing a practice-based research network with physiotherapists in regional Australia

Author

Gleadhill, Connor, Williams, Christopher M., Kamper, Steven J., Bolsewicz, Katarzyna, Delbridge, Andrew, Mahon, Benjamin, Donald, Bruce, Delore, Caitlin, Boettcher, Craig, Renfrew, David, Manvell, Joshua, Dooley, Katherine, Byrne, Michael, Watson, Toby, Makaroff, Andrew, Gibbs, Benedicta, Barnett, Christopher, Corrigan, Michael, Leyland, Murray, Mullen, Nicholas, Gallagher, Ryan, Zelinski, Samuel, Lamond, Steven, Maude, Travis, Davidson, Simon R. E., Robson, Emma, Da Silva, Priscilla Viana, and Manvell, Nicole

Published
2023
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31. Integrated multi-omics for rapid rare disease diagnosis on a national scale

Author

Lunke, Sebastian, Bouffler, Sophie E., Patel, Chirag V., Sandaradura, Sarah A., Wilson, Meredith, Pinner, Jason, Hunter, Matthew F., Barnett, Christopher P., Wallis, Mathew, Kamien, Benjamin, Tan, Tiong Y., Freckmann, Mary-Louise, Chong, Belinda, Phelan, Dean, Francis, David, Kassahn, Karin S., Ha, Thuong, Gao, Song, Arts, Peer, Jackson, Matilda R., Scott, Hamish S., Eggers, Stefanie, Rowley, Simone, Boggs, Kirsten, Rakonjac, Ana, Brett, Gemma R., de Silva, Michelle G., Springer, Amanda, Ward, Michelle, Stallard, Kirsty, Simons, Cas, Conway, Thomas, Halman, Andreas, Van Bergen, Nicole J., Sikora, Tim, Semcesen, Liana N., Stroud, David A., Compton, Alison G., Thorburn, David R., Bell, Katrina M., Sadedin, Simon, North, Kathryn N., Christodoulou, John, and Stark, Zornitza

Published
2023
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32. Complex Heart–Lung Ventilator Emergencies in the CICU

Author

Lopez, Mireia Padilla, Applefeld, Willard, Miller, P. Elliott, Elliott, Andrea, Bennett, Courtney, Lee, Burton, Barnett, Christopher, Solomon, Michael A., Corradi, Francesco, Sionis, Alessandro, Mireles-Cabodevila, Eduardo, Tavazzi, Guido, and Alviar, Carlos L.

Published
2024
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33. Prognostic performance of the IABP-SHOCK II Risk Score among cardiogenic shock subtypes in the critical care cardiology trials network registry

Author

Alviar, Carlos L., Li, Boyangzi K., Keller, Norma M., Bohula-May, Erin, Barnett, Christopher, Berg, David D., Burke, James A., Chaudhry, Sunit-Preet, Daniels, Lori B., DeFilippis, Andrew P., Gerber, Daniel, Horowitz, James, Jentzer, Jacob C., Katrapati, Praneeth, Keeley, Ellen, Lawler, Patrick R., Park, Jeong-Gun, Sinha, Shashank S., Snell, Jeffrey, Solomon, Michael A., Teuteberg, Jeffrey, Katz, Jason N., van Diepen, Sean, and Morrow, David A.

Published
2024
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36. Heart failure related cardiogenic shock: An ISHLT consensus conference content summary

Author

Overgaard, Chris, Teuteberg, Jeffrey, Rosner, Carolyn, Nagpal, Dave, Taimeh, Ziad, Abraham, Jacob, Ton, Van-Khue, Drakos, Stavros, Tehrani, Behnam, Bernhardt, Alexander, Meeran, Talha, Douglas Greig, P., Farrero, Marta, Katz, Jason, Luk, Adriana, Bennett, Courtney, Bertolotti, Alejandro, Tedford, Ryan J., Cogswell, Rebecca, Klein, Liviu, Guerrero-Miranda, Cesar Y., Rampersad, Penelope, Potena, Luciano, Boeken, Udo, Copeland, Hannah, Hall, Shelley, González-Costello, José, Kapur, Navin K., Loforte, Antonio, Burkhoff, Daniel, LePrince, Pascal, Gustafsson, Finn, Uriel, Nir, Kataria, Rachna, Arora, Sonali, Masetti, Marco, Saeed, Diyar, Kanwar, Manreet K., Billia, Filio, Randhawa, Varinder, Cowger, Jennifer A., Barnett, Christopher M., Chih, Sharon, Ensminger, Stephan, Hernandez-Montfort, Jaime, Sinha, Shashank S., Vorovich, Esther, Proudfoot, Alastair, Lim, Hoong S., Blumer, Vanessa, Jennings, Douglas L., Garan, A. Reshad, Renedo, Maria F., Hanff, Thomas C., and Baran, David A.

Published
2024
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37. Consensus statements from the International Society for Heart and Lung Transplantation consensus conference: Heart failure–related cardiogenic shock

Author

Overgaard, Chris, Teuteberg, Jeffrey, Rosner, Carolyn, Nagpal, Dave, Taimeh, Ziad, Abraham, Jacob, Ton, Van-Khue, Drakos, Stavros, Tehrani, Behnam, Bernhardt, Alexander, Meeran, Talha, Douglas Greig, P., Farrero, Marta, Katz, Jason, Luk, Adriana, Bennett, Courtney, Bertolotti, Alejandro, Tedford, Ryan J., Cogswell, Rebecca, Klein, Liviu, Guerrero-Miranda, Cesar Y., Rampersad, Penelope, Potena, Luciano, Boeken, Udo, Copeland, Hannah, Hall, Shelley, González-Costello, José, Kapur, Navin K., Loforte, Antonio, Burkhoff, Daniel, LePrince, Pascal, Gustafsson, Finn, Uriel, Nir, Kataria, Rachna, Arora, Sonali, Masetti, Marco, Saeed, Diyar, Baran, David A., Billia, Filio, Randhawa, Varinder, Cowger, Jennifer A., Barnett, Christopher M., Chih, Sharon, Ensminger, Stephan, Hernandez-Montfort, Jaime, Sinha, Shashank S., Vorovich, Esther, Proudfoot, Alastair, Lim, Hoong Sern, Blumer, Vanessa, Jennings, Douglas L., Garan, A. Reshad, Renedo, Maria Florencia, Hanff, Thomas C., and Kanwar, Manreet K.

Published
2024
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38. Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing

Author

Ball, Megan, Bouffler, Sophie E., Barnett, Christopher B., Freckmann, Mary-Louise, Hunter, Matthew F., Kamien, Benjamin, Kassahn, Karin S., Lunke, Sebastian, Patel, Chirag V., Pinner, Jason, Roscioli, Tony, Sandaradura, Sarah A., Scott, Hamish S., Tan, Tiong Y., Wallis, Mathew, Compton, Alison G., Thorburn, David R., Stark, Zornitza, and Christodoulou, John

Published
2024
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39. Author Correction: Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death

Author

Byrne, Alicia B., Arts, Peer, Ha, Thuong T., Kassahn, Karin S., Pais, Lynn S., O’Donnell-Luria, Anne, Babic, Milena, Frank, Mahalia S. B., Feng, Jinghua, Wang, Paul, Lawrence, David M., Eshraghi, Leila, Arriola, Luis, Toubia, John, Nguyen, Hung, McGillivray, George, Pinner, Jason, McKenzie, Fiona, Morrow, Rebecca, Lipsett, Jill, Manton, Nick, Khong, T. Yee, Moore, Lynette, Liebelt, Jan E., Schreiber, Andreas W., King-Smith, Sarah L., Hardy, Tristan S. E., Jackson, Matilda R., Barnett, Christopher P., and Scott, Hamish S.

Published
2024
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40. Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death

Author

Byrne, Alicia B., Arts, Peer, Ha, Thuong T., Kassahn, Karin S., Pais, Lynn S., O’Donnell-Luria, Anne, Babic, Milena, Frank, Mahalia S. B., Feng, Jinghua, Wang, Paul, Lawrence, David M., Eshraghi, Leila, Arriola, Luis, Toubia, John, Nguyen, Hung, McGillivray, George, Pinner, Jason, McKenzie, Fiona, Morrow, Rebecca, Lipsett, Jill, Manton, Nick, Khong, T. Yee, Moore, Lynette, Liebelt, Jan E., Schreiber, Andreas W., King-Smith, Sarah L., Hardy, Tristan S. E., Jackson, Matilda R., Barnett, Christopher P., and Scott, Hamish S.

Published
2023
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46. Photochemical internalisation to improve the therapeutic indices of chemotherapy drugs and nanoformulations

Author

Barnett, Christopher Marc

Subjects
615.1
Abstract

Photochemical internalisation (PCI) is a novel, minimally-invasive, drug delivery technology that facilitates the delivery of therapeutic molecules into the cytosol of cells. Owing to PCI being initiated by light, treatment is confined to the specific area of illumination and adverse effects in distant tissues are therefore minimised. PCI can enhance the targeted intracellular delivery of therapeutics unable to penetrate cellular membranes and of those sequestered within endosomes and lysosomes whereby they are unable to exert their therapeutic potential. To date, PCI studies have predominantly used immunotoxins as the chemotherapeutic component with relatively few investigating the benefit of PCI in the delivery of clinically-approved small molecule chemotherapy drugs. Three-dimensional (3D) in vitro cell culture models of breast cancer (MDA-MB-231 and MCF-7 cells) and pancreatic cancer (MiaPaCa-2 cells) were used in this work. First, the performance of a range of chemotherapy drugs was tested in 3D breast cancer models with key parameters identified for subsequent use in light treatment experiments. PDT and PCI experiments were then performed and novel PCI-drug combinations compared to PCI of bleomycin (a model PCI chemotherapeutic drug). Excitingly, several promising new PCI-drug combinations were seen to outperform PCI-bleomycin. In particular, PCI-vincristine and PCI delivery of the vinca alkaloids, in general, was seen to perform impressively across all of the treatment outcomes of potency, efficacy, and synergy - as determined by means of a cell viability assay. Key PCI-drug combinations were then taken forward to investigations with alterations made in both PCI regimen and cell culture conditions. Both variations were seen to significantly impact upon PCI treatment outcomes. Finally, PCI-drug combinations were then tested in a 3D model of pancreatic cancer. In addition to this, novel gemcitabine nanoformulations (gemcitabine-squalene and gemcitabine-polymer) were combined in PCI regimens and the former bioconjugate was seen to vastly improve treatment outcomes in both pancreatic and breast cancer models.

Published
2019

48. Role of Critical Care Medicine Training in the Cardiovascular Intensive Care Unit: Survey Responses From Dual Certified Critical Care Cardiologists.

Author

Brusca, Samuel, Barnett, Christopher, Barnhart, Brendan, Weng, Weifeng, Morrow, David, Soble, Jeffrey, Katz, Jason, Wiley, Brandon, van Diepen, Sean, Gomez, Antonio, and Solomon, Michael

Subjects
American Board of Internal Medicine survey, cardiology training, cardiovascular intensive care units, critical care cardiology, Aged, Cardiologists, Cardiovascular Diseases, Certification, Clinical Competence, Critical Care, Education, Medical, Graduate, Female, Humans, Intensive Care Units, Male, Middle Aged, United States
Abstract

Background Cardiovascular intensive care units ( CICUs ) have evolved from coronary care wards into distinct units for critically ill patients with primary cardiac diseases, often suffering from illnesses that cross multiple disciplines. Mounting evidence has demonstrated improved survival with the incorporation of dedicated CICU providers with expertise in critical care medicine ( CCM ). This is the first study to systematically survey dual certified physicians in order to assess the relevance of CCM training to contemporary CICU care. Methods and Results Utilizing American Board of Internal Medicine data through 2014, 397 eligible physicians had obtained initial certification in both cardiovascular disease and CCM . A survey to delineate the role of critical care training in the CICU was provided to these physicians. Among those surveyed, 120 physicians (30%) responded. Dual certified physicians reported frequent use of their CCM skills in the CICU , highlighting ventilator management, multiorgan dysfunction management, end-of-life care, and airway management. The majority (85%) cited these skills as the reason CCM training should be prioritized by future CICU providers. Few (17%) agreed that general cardiology fellowship alone is currently sufficient to care for patients in the modern CICU . Furthermore, there was a consensus that there is an unmet need for cardiologists trained in CCM (70%) and that CICU s should adopt a level system similar to trauma centers (61%). Conclusions Citing specific skills acquired during CCM training, dual certified critical care cardiologists reported that their additional critical care experience was necessary in their practice to effectively deliver care in the modern CICU .

Published
2019

49. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe GN, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, Ross, Robert V MacKenzie, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Noordegraaf, Anton Vonk, Waisfisz, Quinten, and Walsworth, Anna K

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Genetics, Human Genome, Lung, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, HLA-DP alpha-Chains, HLA-DP beta-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, Risk Assessment, SOXF Transcription Factors, Signal Transduction, Survival Analysis, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium, Public Health and Health Services, Other Medical and Health Sciences, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Published
2019

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