In early November 2020, an outbreak of SARS-CoV-2 in Danish mink farms with spill-over back into humans was reported137. Nature https://doi.org/10.1038/s41586-021-03207-w (2021). 26, 453455 (2020). IL-6 is central to the pathogenesis of both HLH and CRS and, by early April 2020, several studies had shown a correlation between IL-6 levels and adverse outcomes in patients with COVID-19 (ref.40). This pandemic has been speculated to be caused by an influenza A virus. Li, W. et al. A comparison of MIS-C with acute COVID-19 and Kawasaki disease (first posted in preprint form in August 2020) noted important differences. 77, 683690 (2020). Invest in the future today. 26, 10371040 (2020). Med. (2002). Infect. Reuters. As such, we have opted to use the preprint date, where available, instead of theofficial publication date for the chronology of the studies that we highlight in our timeline of key discoveries during the first year of the pandemic (Fig. Evidence supporting a zoonotic origin of human coronavirus strain NL63. A study in Brazil found that childless male academics were the least affected with respect to whether they were able to submit manuscripts as planned or meet deadlines, whereas female academics, especially Black women and mothers of younger children, were the most impacted by the pandemic168. New York Times https://nytimes.com/2020/12/30/business/china-vaccine.html (2020). Assessment of SARS-CoV-2 serological tests for the diagnosis of COVID-19 through the evaluation of three immunoassays: Two automated immunoassays (Euroimmun and Abbott) and one rapid lateral flow immunoassay (NG Biotech). NL63-like and 229E-like viruses have been found in bats162,163,164 and viruses related to HKU1 have been found in rats165. WHO Solidarity Trial Consortium, et al. The virus seemed to have potentially adapted to mink by introducing a Y453F mutation into the spike protein RBD (in addition to other mutations). Carvalho, T., Krammer, F. & Iwasaki, A. Inevitably, we have been selective based on the common themes that we feel are the most important take-home messages from the past year; therefore, to some extent, this article represents a personal perspective of our highlights of what we have learnt so far about the immunology of COVID-19. Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines a new era in vaccinology. Science 370, 1339 (2020). Res. Orthogonal SARS-CoV-2 serological assays enable surveillance of low-prevalence communities and reveal durable humoral immunity. Researchers like propose a recommended quarantine length of a minimum of 14 days, suggesting that fatality risks should be estimated using a median time of 13 days between first symptoms and mortality . Cell 181, 14891501.e15 (2020). Nature 584, 450456 (2020). 14 days: a timeline article. Instructional Science, 30, 221-241. J. Virol. Hung, I. F. et al. Pfizer and BioNtech announce vaccine candidate against COVID-19 achieved success in first interim analysis from phase 3 study. Microbiol. 1 p.m.: Hurricane Katrina continues to weaken as it moves farther inland. Funding for FRONTLINE is provided by the Park Foundation and through the. Preprint at medRxiv https://doi.org/10.1101/2020.12.01.20241364 (2020). N. Engl. Students can work in pairs, providing support through cooperative learning as well. UAE announces Sinopharm vaccine has 86% efficacy against COVID-19. Thus, by February 2020, less than 2 months after the first reports, the new disease had been named COVID-19 and three key features had been established that set it apart from the previous coronavirus outbreaks: an efficient person-to-person transmission; the strong signs that people could transmit the virus before, or even without ever, showing symptoms; and its longer incubation period of 5.7 days (pooled mean)13 than that of SARSCoV (mean incubation time of 4.0 days)14 and MERSCoV (range of incubation times from 4.5 to 5.2 days)15. Wassie, G., Azene, A., Bantie, G., Dessie, G. & Aragaw, A. Incubation period of severe acute respiratory syndrome novel coronavirus 2 that causes coronavirus disease 2019: a systematic review and meta-analysis. Here is a timeline aspiring DO students should follow to stay on track during the application. 14 Days - A Timeline | The Storm | FRONTLINE | PBS A timeline of the warnings, some of the decisions leading up to the disaster, and what went wrong with the government's response. Clin. We have a great free tool to create interactive geolocated timelines on myhistro.com I wrote about their use in the classroom here: http://www.myhistro.com/blog/interactive-timelines-for-teachers-and-stud but all that has been said in this article applies to them too. Lynn, S. (1993). Infect. SARS-CoV-2 will likely not be the last coronavirus to cause a pandemic and it is likely that coronaviruses that are now endemic in humans first caused pandemics resulting in large numbers of deaths (Box1). JAMA 324, 663673 (2020). 1. It was proposed that these pre-existing T cells may have been generated in response to seasonal human coronaviruses (HCoVs). Dis. Cavalcanti, A. & Padovani, A. Krammer, F. SARS-CoV-2 vaccines in development. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. This team science approach has propelled the rapid discovery of key aspects of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Fig. Jemima McEvoy. 38, 11741183 (2020). amstar nostalgia 49cc moped; land plane with scarifiers. as co-inventor. While chemotherapy directly targets cancer cells, it also affects other normal rapidly dividing cells in the process. CAS In only a few hours, the storm's strongest winds have increased to about a hundred miles an hour (160 kilometers an hour). 2) Reaction of butan-2-ol with acidified potassium permanganate Autopsy findings and venous thromboembolism in patients with COVID-19. Here's a timeline of a remarkable life. Katrina, at the end of August, killed more than a thousand people and left much of New Orleans and the neighboring coast in ruins. Finally, epidemiological evidence from these early cases indicated that COVID-19 is more likely to affect older males with comorbidities such as chronic diseases, including cardiovascular and cerebrovascular diseases, endocrine system diseases, digestive system diseases, respiratory system diseases, malignant tumours and nervous system diseases12. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. McCrindle, B. W. et al. Dis. The first 12 months of COVID-19: a timeline of immunological - Nature Forever Changed: A Timeline of How COVID Upended Schools Mateus, J. et al. 11:30 a.m.: The National Hurricane Center reports that the hurricane is "rapidly strengthening" as it crosses the Gulf of Mexico's very warm waters. Vijgen, L. et al. Chen, N. et al. Commun. This non-specific effect is mediated by metabolic and epigenetic rewiring in innate immune cells, which leads to increased transcription and improved host defence. Hydroxychloroquine, whichwas widely used early during the pandemic, was shown to have no significant benefits in RCTs as pre-exposure prophylaxis76, as post-exposure prophylaxis77,78, in patients with mild disease who were not hospitalized79, in mild to moderate disease80,81, or in patients hospitalized with moderate or severe disease82,83. Consistent with this, an open-label, phase II clinical trial that randomized 127 participants to receive either combination antiviral therapy (IFN1a injected subcutaneously every other day for 7 days plus lopinavirritonavir) or lopinavirritonavir alone showed that participants who received the combination therapy had more rapid clinical improvement and quicker time to viral control136. Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection. June 2020 also brought important advances for antibody therapeutics. While they are often used as a way to display information in visual form in textbooks as an alternative to written narrative, students can also become more actively engaged in learning the sequence of events in history by constructing timelines themselves. declares no competing interests. At the same time, young investigators, women and under-represented scientists were disproportionately affected by the pandemic. Adv. Pinpoint the problem a struggling reader is having and discover ways to help. Virol. A pneumonia outbreak associated with a new coronavirus of probable bat origin. The other three endemic coronaviruses in humans NL63, 229E (both alphacoronaviruses) and HKU1 (betacoronavirus) are speculated to also be of zoonotic origin161. Pfizer https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against (2020). Characteristics of SARS-CoV-2 and COVID-19, Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine, A systematic review of SARS-CoV-2 vaccine candidates, The trinity of COVID-19: immunity, inflammation and intervention, https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200228-sitrep-39-covid-19.pdf?sfvrsn=5bbf3e7d_4, https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participant-dosed-nih-led-phase-1-study, https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00, https://doi.org/10.1101/2021.01.07.21249390, https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103134, https://doi.org/10.1101/2020.12.01.20241364, https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its-mrna-vaccine, https://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_biontech_dose_first_participants_in_the_u_s_as_part_of_global_covid_19_mrna_vaccine_development_program, https://doi.org/10.1101/2020.11.06.20227215, https://doi.org/10.1101/2020.07.18.20155374, https://doi.org/10.1101/2020.11.15.383661, https://www.recoverytrial.net/news/statement-from-the-recovery-trial-chief-investigators-15-january-2021-recovery-trial-closes-recruitment-to-convalescent-plasma-treatment-for-patients-hospitalised-with-covid-19, https://doi.org/10.1101/2020.10.21.20216192, https://doi.org/10.1101/2020.12.28.20248807, https://doi.org/10.1101/2020.12.10.20247205, https://doi.org/10.1101/2021.01.21.21249176, https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563, https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trial, https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3, https://doi.org/10.1038/s41586-021-03207-w, https://doi.org/10.1101/2020.12.28.424451, https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against, https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy, https://sputnikvaccine.com/newsroom/pressreleases/second-interim-analysis-of-clinical-trial-data-showed-a-91-4-efficacy-for-the-sputnik-v-vaccine-on-d/, https://nytimes.com/2020/12/30/business/china-vaccine.html, https://asia.nikkei.com/Spotlight/Coronavirus/UAE-announces-Sinopharm-vaccine-has-86-efficacy-against-COVID-19, https://www.reuters.com/article/us-health-coronavirus-china-vaccine/cansinos-covid-19-vaccine-candidate-approved-for-military-use-in-china-idUSKBN2400DZ, https://doi.org/10.1101/2020.07.04.187583, A strategy for evaluating potential antiviral resistance to small molecule drugs and application to SARS-CoV-2, Microbead-based extracorporeal immuno-affinity virus capture: a feasibility study to address the SARS-CoV-2 pandemic, Timing of surgery and elective perioperative management of patients with previous SARS-CoV-2 infection: a SIAARTI expert consensus statement, Summarising data and factors associated with COVID-19 related conspiracy theories in the first year of the pandemic: a systematic review and narrative synthesis, Moving toward a common goal via cross-sector collaboration: lessons learned from SARS to COVID-19 in Singapore, Cancel Its center is about 45 miles (70 kilometers) northwest of Key Largo, Florida. A study by Ng et al.72, first posted as a preprint in May 2020, detected cross-reactive antibodies against SARS-CoV-2 in pre-pandemic sera from the UK, particularly in children and adolescents 616 years of age, having a high seroprevalence of 62%. June 15, 2020: The 14-day travel requirement for out-of-state travelers from coronavirus hot spot areas expired. Several other groups had reported a low frequency of somatic mutations in SARS-CoV-2 neutralizing antibodies101,102,103, which suggests that germline-encoded B cell receptor sequences have a sufficiently high affinity for the spike protein to limit antigen access to the germinal centre. Levstik, L. (1991). Beigel, J. H. et al. Use reader response questions and prompts to discuss the book and connect the concept of birth date to each student's own life: "What do you know about what happened on the day you were born?" By the end of March, the U.S. has more COVID-19 cases and deaths than any other country. Preprint at medRxiv https://doi.org/10.1101/2020.12.28.20248807 (2021). Nat. Analysis of the B cells specific for SARS-CoV-2 spike protein in a single patient 21 days after the onset of clinical disease found only a small number of somatic mutations, even though the patient had high serum titres of anti-spike antibodies100. Gender, race and parenthood impact academic productivity during the COVID-19 pandemic: from survey to action. Absence of SARS-CoV-2 neutralizing activity in pre-pandemic sera from individuals with recent seasonal coronavirus infection. CanSinos COVID-19 vaccine candidate approved for military use in China. Discuss the book using reader response questions and prompts such as "What would a timeline of your life look like? There are many lessons to be learned from this pandemic, which will hopefully prepare us better for future pandemics. JAMA 324, 21652176 (2020). 14 days: a timeline article. 2 March Yet the weather was to throw German plans into disarray. Science 69, 818823 (2020). SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation. A pandemic of respiratory disease known as the Russian flu occurred in 1889 and 1890 and caused approximately one million deaths globally. A framework for designing interactive multimedia to scaffold young children's understanding of historical chronology. Over the course of November and December 2020, further vaccine effectiveness data with viral-vectored and inactivated vaccine candidates were released, ranging in the 8090% effectiveness range152,153,154,155. d | Early post-exposure prophylaxis with recombinant type I interferon can reduce the viral load of SARS-CoV-2 and hasten recovery. Codenamed Adlerangriff (Eagle Attack), it was due to commence on 13 August. B. Questions about reading, writing, dyslexia and more, Classroom StrategiesResearch-based teaching strategies, Reading Basics These autoantibodies had interferon-neutralizing activity in vitro. Moderna announces positive interim phase 1 data for its mRNA vaccine (mRNA-1273) against novel coronavirus. Both Y453F and N439K have been shown to affect neutralization by some SARS-CoV-2-specific monoclonal antibodies104, although other antibodies are unaffected, which makes it unlikely that these two mutations alone would impair vaccine effectiveness. N. Engl. 89, 3076 (2015). Children, medicated action, and the tools of historical time. Updated: Apr 21, 2020. Bats and agaves make tequila possibleand theyre both at risk, This empress was the most dangerous woman in Rome. Garvin, M. R. et al. Ba1ton, K. C. (2002). Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with a high attack rate. Rev. Further research is needed to understand whether pre-existing cross-reactive antibodies and T cells can confer protection in different age groups and/or geographical locations. Next came the cave men. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. But there weren't any castles or Popsicle stands yet. Science 369, 806 (2020). Baum et al.104, from Regeneron Pharmaceuticals, published a very detailed paper about the therapeutic monoclonal antibodies that they had in development and the viral escape that these monoclonal antibodies could drive. Nature 584, 115119 (2020). The use of dexamethasone for up to 10 days resulted in lower mortality at 28 days than usual care in patients who were receiving invasive mechanical ventilation and in those who were receiving oxygen. . Nat. Another way to hide past posts is to limit specific people or lists of people from viewing what others have posted to The ship itself contained approximately 3,500 people and was to undergo This score is calculated based on Mean time to failure and Total usage duration (14 days). Provided by the Springer Nature SharedIt content-sharing initiative, Journal of Anesthesia, Analgesia and Critical Care (2022), Nature Reviews Immunology (Nat Rev Immunol) Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Effective Use of Timelines in Nonfiction Articles - Writers Write Autoimmunity to the lung protective phospholipid-binding protein Annexin A2 predicts mortality among hospitalized COVID-19 patients. - With 93 new cases, the nation's total increased to 191. N. Engl. 11, 3810 (2020). Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Currently, there are 22 randomized clinical trials ongoing to test whether BCG vaccination can confer protection against SARS-CoV-2 infection. 14 days: a timeline article - curiosbettysa.com : he has previously published work on influenza virus vaccines with S. Gilbert (University of Oxford), has consulted for Curevac, Merck and Pfizer (before 2020), is currently consulting for Avimex (Mexico) and Seqirus (Australia), his laboratory is collaborating with Pfizer on animal models of SARS-CoV-2, his laboratory is collaborating with N. Pardi at the University of Pennsylvania on mRNA vaccines against SARS-CoV-2, his laboratory was working in the past with GlaxoSmithKline on the development of influenza virus vaccines, and two of his mentees have recently joined Moderna. https://doi.org/10.1093/cid/ciaa1571 (2020). Huang et al.7 also reported that 26 of the 41 patients had lymphopenia and that those admitted to the ICU had increased plasma levels of cytokines and chemokines, specifically IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (GCSF; also known as CSF3), CC-chemokine ligand 2 (CCL2; also known as MCP1) and tumour necrosis factor (TNF). In addition, Chen et al.38 showed that patients who were critically ill had significantly higher IL-6 concentrations than patients with moderate disease. 384, 693704 (2021). Asecond study of patients with COVID-19 in intensive care found that mortality for 397 individuals in the placebo group was 35.8% compared with 28% in 350 patients treated with tocilizumab and 22% in 45patients who received sarilumab45. Moore, J. Amanat, F. & Krammer, F. SARS-CoV-2 vaccines: status report. Type I interferon induced late during infection may be detrimental in driving pathological responses. A. et al. Yeager, E. A., & Terzian, S. (2007). Del Valle, D. M. et al. Science 369, 812 (2020). Google Scholar. Based on the results from non-human primate models, most of the vaccines in development, while protecting the lungs and preventing disease, will still allow for replication of the virus in the upper respiratory tract158. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. A timeline of international air crashes from 1998 to the present. They can also create parallel timelines by continuing to add to their own personal timeline, as well as adding current events in the world. Copyright 1996-2015 National Geographic SocietyCopyright 2015-2023 National Geographic Partners, LLC. The groundbreaking promise of cellular housekeeping. Moderna https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its-mrna-vaccine (2020). 383, 26032615 (2020). In addition, the question of durability of the antibody response to SARS-CoV-2 was addressed by several studies in late July and August 2020, which showed that the antibody response is indeed normal and long lasting93,94,95,96,97,98,99. He's also worried that many new residents of Biloxi have no idea what they may soon be facing. https://doi.org/10.1038/s41577-021-00522-1, DOI: https://doi.org/10.1038/s41577-021-00522-1. Pfizers own Phase 3 trials with 40,000 people determined that the effects of the first dose kicked in after 11 days. reactions https://doi.org/10.1093/cid/ciaa1803 (2020). The advisory notes that the season's 12th tropical depression has formed over the Bahamas. 14 days: a timeline article - lovelybrations.com Protoc. Norway holds out until June 9. Which travel companies promote harmful wildlife activities? Although multiple compassionate use, observational and retrospective studies reported beneficial effects of tocilizumab in patients with COVID-19, randomized controlled trials have not shown major effects on survival43. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. Second death in Turkey - Turkey confirmed its second death in a 61-year-old male. Verdoni, L. et al. WHO. Infect. Huynh, J. et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome cCoronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. Staniscuaski, F. et al. 14 days: a timeline article - mashroubs.com The first 12 months of COVID-19: a timeline of immunological insights. Provide equations/ "Oh, that's a tricky piece!" The timing and route of the interferon therapy seem to be key, as an interim report from the WHO Solidarity Trial, an open label trial in which patients of all stages of disease who were hospitalized were randomly assigned to receive subcutaneous IFN1a or other repurposed antivirals, showed little or no effect of interferon therapy on overall mortality, initiation of ventilation or duration of hospital stay85. Google Scholar. For the virus that causes COVID-19 its official name is SARS-CoV-2 researchers have found that the typical incubation period is about five days. An important early finding was that SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter host cells. Brouwer, P. J. M. et al. Lancet 395, 514523 (2020). Sanofi https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00 (2020). Libster, R. et al. All patients developed pneumonia, 13 required treatment in an intensive care unit (ICU) and 6 had died by the time the study was published on 24 January 2020 (ref.7). Neurologic features in severe SARS-CoV-2 infection. Tips from experts on how to help your children with reading and writing at home. Preprint at medRxiv https://doi.org/10.1101/2020.11.06.20227215 (2020). Chan, J. F.-W. et al. How do these results fit with other reports showing protective versus pathogenic roles of type I and type III interferons in COVID-19 (Fig. answered Materials Computer with Internet access 14 Days: A Timeline article Assignment Instructions For this project, you are expected to submit two (2) items: 1. What if we could clean them out? Read aloud On the Day You Were Born, by Debra Frasier (2005). Jan. 30, 2021. "A lot of the live-aboards [people living on houseboats] in Boot Key Harbor were surprised to find their boats in new spots.". By contrast, none of the 663 patients with asymptomatic or mild COVID-19 and only 4 of the 1,227 (0.3%) healthy donors had auto-antibodies to type I interferon. Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. A calendar is convenient for regulating civil life and religious observances and for historical and scientific purposes. One early assumption was that, as is the case for most acute respiratory virus infections, infection with SARS-CoV-2 would induce a neutralizing antibody response. Champalimaud Center for the Unknown, Lisbon, Portugal, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA, Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA, Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA, Howard Hughes Medical Institute, Chevy Chase, MD, USA, You can also search for this author in Materials Computer with Internet access 14 Days: A Timeline article Assignment Instructions For this project, you are expected to submit two (2) items: 1. The weather system is about 350 miles (560 kilometers) east of Miami. On July 15, 2008, she was reported missing in a 9-1-1 call made by Cindy, who said she had not seen Caylee for 31 days and that Casey's car smelled In earlier civilizations and among primitive peoples, where there was less communication between different settlements or groups, different methods of reckoning the day presented no difficulties. Get the most important science stories of the day, free in your inbox. Sanofi and Regeneron provide update on U.S. phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients. Dates were more useful for older students in Grades 3 and 4, and this ability increased in Grades 5 and 6 as students could match dates with specific pictures. Nat. 91k . From print awareness to comprehension, Reading 101 Course . These include antibodies to cytokines, interferons, chemokines and leukocytes, which could directly affect the nature of antiviral immunity as well as antibodies to tissue-specific antigens expressed in the central nervous system, vasculature, connective tissues, cardiac tissue, hepatic tissue and intestinal tract, which could potentially cause antibody-mediated organ damage124. Emerg. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. Authentic assessment of timelines could include a guideline for the elements expected in each timeline, which could also serve as a self-editing checklist for students as they produce the timeline. 26, 14781488 (2020). Nature 583, 290295 (2020). . J. Clin. Long, Q.-X. 1. J. Med. 14 days a timeline article. Borba, M. G. S. et al. How to Serve a Tenant. "I have always imagined that paradise will be a kind of library." Despite decades of research, the cause of Kawasaki disease is unknown52, although some evidence suggests that autoreactive antibodies induced by an acute viral infection could lead to inflammation and vascular damage.
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