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      Multimodality molecular imaging of the alveolar-capillary barrier in lung disease using albumin based optical and PET tracers

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          Abstract

          Inflammatory changes caused by viruses, bacteria, exposure to toxins, commonly used drugs and even surgical intervention have the potential of causing abnormal epithelial permeability, which is manifest as infiltrative processes on computed tomography (CT), including the widespread infiltrates seen in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). We utilized a previously published mouse model of ARDS, intranasal delivery of LPS, to induce the alveolar-capillary barrier permeability seen in lung disease. We intravenously injected mice with Cy7 or 68-Gallium ( 68Ga) labeled mouse albumin and imaged using optical imaging (OI)/CT and PET. We observed significantly increased lung levels of Cy7-albumin on 3D OI/CT, which matched the abnormal appearance on microCT. This uptake correlated with fluorescence seen on sectioned lungs. To examine the translational potential of these findings, we radiolabeled albumin with 68Ga. We found that in mice with LPS-induced lung injury, 68Ga-albumin PET correlated with our optical imaging findings and demonstrated abnormal activity in the lung fields, indicative of abnormal epithelial permeability. These findings indicate 68Ga-albumin can be utilized as a sensitive translational radiotracer for quantifying the abnormal epithelial permeability that is seen in various lung pathologies, including COVID-19 induced pneumonia and ARDS. The ability to use Cy7-albumin 3D OI/CT imaging as a preclinical translational surrogate for 68Ga-albumin offers an accessible high throughput means to rapidly screen potential therapeutics against lung diseases that clinically manifest with endothelial permeability.

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          Most cited references14

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

            Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.
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              Recognition of microorganisms and activation of the immune response.

              The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.
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                Author and article information

                Contributors
                am4754@cumc.columbia.edu
                Journal
                Mol Biomed
                Molecular Biomedicine
                Springer Singapore (Singapore )
                2662-8651
                20 December 2020
                20 December 2020
                2020
                : 1
                : 1
                : 17
                Affiliations
                [1 ]GRID grid.21729.3f, ISNI 0000000419368729, Department of Radiology, , Columbia University Irving Medical Center, ; 722 W. 168th St., New York, NY 10032 USA
                [2 ]GRID grid.239585.0, ISNI 0000 0001 2285 2675, Center for LAM and Rare Lung Diseases, Department of Anesthesiology, , Columbia University Medical Center, ; 722 W. 168th St., New York, NY 10032 USA
                Article
                20
                10.1186/s43556-020-00020-1
                7749789
                ffedcbd8-8b8e-4a2c-b8fd-dc84cb0387c7
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 September 2020
                : 20 November 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100006108, National Center for Advancing Translational Sciences;
                Award ID: UL1TR001873
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                pet,68ga-albumin,ards,covid
                pet, 68ga-albumin, ards, covid

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