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      Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation

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          The importance of circadian factors in managing patients is poorly understood. We present two retrospective cohort studies showing that lungs reperfused between 4 and 8 AM have a higher incidence (OR 1.12; 95% CI 1.03 to 1.21; p=0.01) of primary graft dysfunction (PGD) in the first 72 hours after transplantation. Cooling of the donor lung, occurring during organ preservation, shifts the donor circadian clock causing desynchrony with the recipient. The clock protein REV-ERBα directly regulates PGD biomarkers explaining this circadian regulation while also allowing them to be manipulated with synthetic REV-ERB ligands.

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          Most cited references 6

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          Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation.

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            Primary graft dysfunction.

            Primary graft dysfunction (PGD) is a syndrome encompassing a spectrum of mild to severe lung injury that occurs within the first 72 hours after lung transplantation. PGD is characterized by pulmonary edema with diffuse alveolar damage that manifests clinically as progressive hypoxemia with radiographic pulmonary infiltrates. In recent years, new knowledge has been generated on risks and mechanisms of PGD. Following ischemia and reperfusion, inflammatory and immunological injury-repair responses appear to be key controlling mechanisms. In addition, PGD has a significant impact on short- and long-term outcomes; therefore, the choice of donor organ is impacted by this potential adverse consequence. Improved methods of reducing PGD risk and efforts to safely expand the pool are being developed. Ex vivo lung perfusion is a strategy that may improve risk assessment and become a promising platform to implement treatment interventions to prevent PGD. This review details recent updates in the epidemiology, pathophysiology, molecular and genetic biomarkers, and state-of-the-art technical developments affecting PGD.
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              Measuring synchrony in the mammalian central circadian circuit.

              Circadian clocks control daily rhythms in physiology and behavior across all phyla. These rhythms are intrinsic to individual cells that must synchronize to their environment and to each other to anticipate daily events. Recent advances in recording from large numbers of cells for many circadian cycles have enabled researchers to begin to evaluate the mechanisms and consequences of intercellular circadian synchrony. Consequently, methods have been adapted to estimate the period, phase, and amplitude of individual circadian cells and calculate synchrony between cells. Stable synchronization requires that the cells share a common period. As a result, synchronized cells maintain constant phase relationships to each (e.g., with cell 1 peaking an hour before cell 2 each cycle). This chapter reviews how circadian rhythms are recorded from single mammalian cells and details methods for measuring their period and phase synchrony. These methods have been useful, for example, in showing that specific neuropeptides are essential to maintain synchrony among circadian cells.

                Author and article information

                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                April 2019
                9 October 2018
                : 74
                : 4
                : 413-416
                [1 ] departmentFaculty of Biology, Medicine and Health , Manchester Academic Health Sciences Centre, The University of Manchester , Manchester, UK
                [2 ] departmentDepartment of Respiratory Medicine , Manchester University NHS Foundation Trust , Manchester, UK
                [3 ] departmentDepartment of Cardiothoracic Surgery , Manchester University NHS Foundation Trust , Manchester, UK
                [4 ] departmentThe Toronto Lung Transplant Program , Toronto General Hospital, University Health Network, University of Toronto , Toronto, Ontario, Canada
                [5 ] departmentNIHR Oxford Biomedical Research Centre , John Radcliffe Hospital , Oxford, UK
                [6 ] departmentOxford Centre for Diabetes, Endocrinology and Metabolism , University of Oxford , Oxford, UK
                Author notes
                [Correspondence to ] Professor David W Ray and Dr John F Blaikley, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, UK; david.w.ray@ , john.blaikley@
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

                Funded by: FundRef, Arthritis Research UK;
                Funded by: FundRef, Wellcome Trust;
                Funded by: FundRef, Medical Research Council;
                Funded by: FundRef, Asthma UK;
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                macrophage biology, lung transplantation


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