Corpus overview


MeSH Disease

Human Phenotype


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    Towards the design of multiepitope-based peptide vaccine candidate against SARS-CoV-2

    Authors: Hasanain Abdulhameed Odhar; Salam Waheed Ahjel; Suhad Sami Humadi

    doi:10.1101/2020.07.07.186122 Date: 2020-07-08

    Coronavirus disease MESHD 2019 is a current pandemic health threat especially for elderly TRANS patients with comorbidities. This respiratory disease MESHD is caused by a beta coronavirus known as severe acute respiratory syndrome MESHD coronavirus 2. The disease MESHD can progress into acute respiratory distress HP syndrome MESHD that can be fatal. Currently, no specific drug or vaccine are available to combat this pandemic outbreak. Social distancing and lockdown have been enforced in many places worldwide. The spike protein of coronavirus 2 is essential for viral entry into host target cells via interaction with angiotensin converting enzyme 2. This viral protein is considered a potential target for design and development of a drug or vaccine. Previously, we have reported several potential epitopes on coronavirus 2 spike protein with high antigenicity, low allergenicity and good stability against specified proteases. In the current study, we have constructed and evaluated a peptide vaccine from these potential epitopes by using in silico approach. This construct is predicted to have a protective immunogenicity, low allergenicity and good stability with minor structural flaws in model build. The population coverage of the used T-cells epitopes is believed to be high according to the employed restricted alleles. The vaccine construct can elicit efficient and long-lasting immune response as appeared through simulation analysis. This multiepitope-based peptide vaccine may represent a potential candidate against coronavirus 2. However, further in vitro and in vivo verification are required.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Disease MESHD severity-specific neutrophil signatures in blood SERO transcriptomes stratify COVID-19 patients

    Authors: Thomas Ulas; Lea Seep; Jona Schulte-Schrepping; Elena De Domenico; Simachew Mengiste; Heidi Theis; Michael Kraut; Matthias Becker; Jannik Gierlich; Lena Lenkeit; Anna Drews; Martina van Uelft; Kilian Dahm; Shobhit Agrawal; Ioanna D Gemuend; Arik Horne; Lisa Holsten; Miriam Herbert; Charlotte Kroeger; Theodorw S Kapellos; Tal Pecht; Rainer Knoll; Kevin Bassler; Nico Reusch; Lorenzo Bonaguro; Melanie Nuesch-Germano; Marie Oestreich; Anna Christin Aschenbrenner; Joachim L Schultze; Matthijs Kox; Niklas Bruse; Peter Pickkers; Jelle Gerretsen; Mihai. G Netea; Frank van de Veerdonk; Jacob Nattermann; Benjamin Kraemer; Jan Raabe; Michael ToVinh; Christoph Hoffmeister; Gereon J Rieke; Verena Keitel; Monique MB Breteler; Ahmad N Aziz; Valentina Talevi; Evangelos J Giamarellos-Bourboulis; Maria Mouktaroudi; Nikolaos Antonakos; Konstantina Gkizeli; Maria Saridaki; Sarantia Doulou; Nikoletta Rovina; Antonia Koutsoukou

    doi:10.1101/2020.07.07.20148395 Date: 2020-07-08

    The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic TRANS, mild respiratory tract infection MESHD respiratory tract infection HP, to severe cases with acute respiratory distress HP syndrome MESHD, respiratory failure HP, and death MESHD. Reports on a dysregulated immune system in the severe cases calls for a better characterization and understanding of the changes in the immune system. Here, we profiled whole blood SERO transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood SERO transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 11 COVID-19 patients. Comparison of COVID-19 blood SERO transcriptomes with those of a collection of over 2,600 samples derived from 11 different viral infections MESHD, inflammatory diseases MESHD and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

    Characteristics and outcomes of Acute Respiratory Distress HP Syndrome MESHD related to COVID-19 in Belgian and French Intensive Care Units according to antiviral strategies. The COVADIS multicenter observational study.

    Authors: David Grimaldi; Nadia Aissaoui; Gauthier Blonz; Giuseppe Carbutti; Romain Courcelle; Stephane Gaudry; Julien Higny; Geoffrey Horlait; Sami Hraiech; Laurent Lefebvre; Francois Lejeune; Andre Ly; Michael Piagnerelli; Bertrand Sauneuf; Nicolas Serck; Thibaud Soumagne; Piotr Szychowiak; Julien Textoris; Benoit Vandenbunder; Christophe Vinsonneau; Jean Baptiste Lascarrou

    doi:10.1101/2020.06.28.20141911 Date: 2020-07-07

    Background Limited data are available for antiviral therapy efficacy especially for the most severe patients under mechanical ventilation suffering from Covid-19 related Acute Respiratory Distress HP Syndrome MESHD (ARDS). Methods Observational multicenter cohort of patients with moderate to severe Covid-19 ARDS, comparing antiviral strategies (none, hydroxychloroquine (HCQ), lopinavir/ritonavir (L/R), others (combination or remdesivir). The primary end-point was the day-28 ventilator free days (VFD), patients which died before d28 were considered as having 0 VFD. The variable was dichotomized in patients still ventilated or dead at day 28 vs patients being extubated and alive at day 28 (VFD = or > 0). Results We analyzed 376 patients (80 with standard of care (SOC), 49 treated with L/R, 197 with HCQ, and 50 others). The median number of d28-VFD was 0 (IQR 0-13) and was different across the different groups (P=0.01), the SOC patients having the highest d28-VFD. A multivariate logistic regression including antiviral strategies, showed that age TRANS (OR 0.95 CI95%:0.93-0.98), male TRANS gender TRANS (OR 0.53 CI95%:0.31-0.93), Charlson score (OR 0.85 CI95%:0.73-0.99) and plateau pressure (OR 0.94 CI95%:0.88-0.99) were associated with having 0 d28-VFD whereas P/F ratio (OR 1.005 CI95%:1.001-1.010) was associated with having > or = 1 d28-VFD (ie. being extubated and alive). Acute kidney injury MESHD Acute kidney injury HP (AKI) was frequent (64%), its incidence was different across the patients groups (P=0.01). In a post-hoc logistic multivariate regression apart from demographics characteristics and comorbidities, the use of L/R (administered to 81 of 376 patients) was associated with occurrence of AKI (OR 2.07 CI95%:1.17-3.66) and need for renal replacement therapy (RRT). Conclusion In this observational study of moderate to severe Covid-19 ARDS patients, we did not observed a benefit of treating patients with any specific antiviral treatment. We observed an association between L/R treatment and occurrence of AKI and need for RRT.

    Dual-Histamine Blockade with Cetirizine - Famotidine Reduces Pulmonary Symptoms in COVID-19 Patients

    Authors: Reed B Hogan II; Reed B Hogan III; Tim Cannon; Maria Rappi; John Studdard; Doug Paul; Thomas P Dooley

    doi:10.1101/2020.06.30.20137752 Date: 2020-07-06

    Background: The COVID-19 pandemic due to SARS-CoV-2 infection MESHD can produce Acute Respiratory Distress HP Syndrome MESHD as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation MESHD and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria MESHD urticaria HP, and might reduce the histamine-mediated pulmonary cytokine storm in COVID-19. Can a combination of Histamine-1 and Histamine-2 blockers improve COVID-19 inpatient outcomes? Methods: A physician-sponsored cohort study of cetirizine and famotidine was performed in hospitalized patients with severe to critical pulmonary symptoms. Pulmonologists led the inpatient care in a single medical center of 110 high-acuity patients that were treated with cetirizine 10 mg and famotidine 20 mg b.i.d. plus standard-of-care. Results: Of all patients, including those with Do Not Resuscitate directives, receiving the dual-histamine blockade for at least 48 hours, the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 hours of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization. The drug combination exhibited reductions in symptom progression when compared to published reports of COVID-19 patients. Concomitant medications were assessed and hydroxychloroquine was correlated with worse outcomes. Conclusions: This physician-sponsored cohort study of cetirizine and famotidine provides proof-of-concept of a new safe and effective method to reduce the progression in symptom severity, presumably by minimizing the histamine-mediated cytokine storm. Further clinical studies in COVID-19 are warranted of the repurposed off-label combination of two historically-safe histamine blockers.

    Prior diagnoses and medications as risk factors for COVID-19 in a Los Angeles Health System

    Authors: Timothy S Chang; Yi Ding; Malika K Freund; Ruth Johnson; Tommer Schwarz; Julie M Yabu; Chad Hazlett; Jeffrey N Chiang; Ami Wulf; - UCLA Health Data Mart Working Group; Daniel H Geschwind; Manish J Butte; Bogdan Pasaniuc

    doi:10.1101/2020.07.03.20145581 Date: 2020-07-04

    With the continuing coronavirus disease MESHD 2019 (COVID-19) pandemic coupled with phased reopening, it is critical to identify risk factors associated with susceptibility and severity of disease MESHD in a diverse population to help shape government policies, guide clinical decision making, and prioritize future COVID-19 research. In this retrospective case-control study, we used de-identified electronic health records (EHR) from the University of California Los Angeles (UCLA) Health System between March 9th, 2020 and June 14th, 2020 to identify risk factors for COVID-19 susceptibility (severe acute respiratory distress HP syndrome MESHD coronavirus 2 (SARS-CoV-2) PCR test positive), inpatient admission, and severe outcomes (treatment in an intensive care unit or intubation). Of the 26,602 individuals tested by PCR for SARS-CoV-2, 992 were COVID-19 positive (3.7% of Tested), 220 were admitted in the hospital (22% of COVID-19 positive), and 77 had a severe outcome (35% of Inpatient). Consistent with previous studies, males TRANS and individuals older than 65 years old had increased risk of inpatient admission. Notably, individuals self-identifying as Hispanic or Latino constituted an increasing percentage of COVID-19 patients as disease MESHD severity escalated, comprising 24% of those testing positive, but 40% of those with a severe outcome, a disparity that remained after correcting for medical co-morbidities. Cardiovascular disease MESHD, hypertension, and renal MESHD hypertension HP disease MESHD were premorbid risk factors present before SARS-CoV-2 PCR testing associated with COVID-19 susceptibility. Less well-established risk factors for COVID-19 susceptibility included pre-existing dementia MESHD dementia HP (odds ratio (OR) 5.2 [3.2-8.3], p=2.6 x 10-10), mental health conditions (depression OR 2.1 [1.6-2.8], p=1.1 x 10-6) and vitamin D deficiency MESHD (OR 1.8 [1.4-2.2], p=5.7 x 10-6). Renal diseases MESHD including end-stage renal disease MESHD and anemia MESHD anemia HP due to chronic renal disease MESHD were the predominant premorbid risk factors for COVID-19 inpatient admission. Other less established risk factors for COVID-19 inpatient admission included previous renal transplant (OR 9.7 [2.8-39], p=3.2x10-4) and disorders of the immune system (OR 6.0 [2.3, 16], p=2.7x10-4). Prior use of oral steroid medications was associated with decreased COVID-19 positive testing risk (OR 0.61 [0.45, 0.81], p=4.3x10-4), but increased inpatient admission risk (OR 4.5 [2.3, 8.9], p=1.8x10-5). We did not observe that prior use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers increased the risk of testing positive for SARS-CoV-2, being admitted to the hospital, or having a severe outcome. This study involving direct EHR extraction identified known and less well-established demographics, and prior diagnoses and medications as risk factors for COVID-19 susceptibility and inpatient admission. Knowledge of these risk factors including marked ethnic disparities observed in disease MESHD severity should guide government policies, identify at-risk populations, inform clinical decision making, and prioritize future COVID-19 research.

    Plasma SERO IL-6 Levels following Corticosteroid Therapy as an Indicator of ICU Length of Stay in Critically ill COVID-19 Patients

    Authors: Samir Awasthi; Tyler Wagner; AJ Venkatakrishnan; Arjun Puranik; Matthew Hurchik; Vineet Agarwal; Ian Conrad; Christian Kirkup; Raman Arunachalam; John O'Horo; Walter Kremers; Rahul Kashyap; William Morice; John Halamka; Amy W Williams; William A Faubion; Andrew D Badley; Gregory J Gores; Venky Soundararajan

    doi:10.1101/2020.07.02.20144733 Date: 2020-07-03

    Intensive Care Unit (ICU) admissions and mortality in severe COVID-19 patients are driven by cytokine storms and acute respiratory distress HP syndrome MESHD (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays superior 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. Among 16 patients with plasma SERO IL-6 measurement post-corticosteroid administration, a higher proportion of patients with an IL-6 value over 10 pg/mL have worse outcomes (i.e. ICU Length of Stay > 15 days or death MESHD) when compared to 41 patients treated with non-corticosteroid drugs including antivirals, tocilizumab, azithromycin, and hydroxychloroquine (p-value = 0.0024). Given this unexpected clinical association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the Glucocorticoid Receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome MESHD (CRS). Examining single cell RNA-seq data from bronchoalveolar lavage fluid of severe COVID-19 patients and nearly 2 million human cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express both NR3C1 and IL-6. The mechanism of Glucocorticoid Receptor (GR) agonists mitigating pulmonary and multi-organ inflammation MESHD in some COVID-19 patients with respiratory failure HP, may be in part due to their successful antagonism of IL-6 production within lung macrophages and vasculature.

    Injury-Prone: Peripheral nerve injuries MESHD associated with prone positioning for COVID-19-related acute respiratory distress HP syndrome MESHD

    Authors: George R. Malik; Alexis R. Wolfe; Rachna Soriano; Leslie Rydberg; Lisa F. Wolfe; Swati Deshmukh; Jason H. Ko; Ryan P. Nussbaum; Prakash Jayabalan; James M. Walter; Colin K. Franz

    doi:10.1101/2020.07.01.20144436 Date: 2020-07-02

    Patients with Coronavirus disease MESHD 2019 (COVID-19) who require invasive mechanical ventilation frequently meet the acute respiratory distress HP syndrome MESHD (ARDS) diagnostic criteria. Hospitals based in the United States have been incorporating prone positioning (PP) into the COVID-19-related ARDS treatment plan at a higher rate than normal. Here, we describe 11 patients admitted to a single inpatient rehabilitation hospital who were subsequently diagnosed with acquired focal/multifocal peripheral nerve injury MESHD (PNI) in association with the use of PP for COVID-19-related ARDS. The reason for the high rate of PNI associated with PP in COVID-19 ARDS is likely multifactorial, but may include an underlying state of hyperinflammation and hypercoagulability HP already linked to other the neurological sequelae of COVID-19. Physicians must be aware of this elevated susceptibility to PNI in severe COVID-19 and refined standard PP protocols in order to reduce the risk.

    A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury MESHD during the COVID-19 pandemic

    Authors: Maria Malimova; Abhigyan Satyam; Michelle Melanson; Brian T. Chamberlain; Seth L. Alper; Jean Santos; Juan Gutierrez; Ayshwarya Subramanian; Elizabeth Grinkevich; Estefania Reyes Bricio; Abbe Clark; Rebecca Thompson; Jamie Marshall; Juan Lorenzo Pablo; Julie Roignot; Maheswarareddy Emani; Matthew Racette; Valeria Padovano; Stephen P. McAdoo; Frederick W.K. Tam; Lucienne Ronco; Florence Wagner; George C. Tsokos; Jillian L. Shaw

    doi:10.1101/2020.06.30.180380 Date: 2020-06-30

    Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease MESHD arising from SARS-CoV-2 infection MESHD. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury MESHD (ALI) and respiratory distress HP syndrome MESHD (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia MESHD thrombocytopenia HP, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury MESHD.

    SARS-CoV-2 Infection MESHD of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

    Authors: Jessie Huang; Adam J Hume; Kristine M Abo; Rhiannon B Werder; Carlos Villacorta-Martin; Konstantinos D Alysandratos; Mary Lou Beermann; Judith Olejnik; Ellen Suder; Esther Bullitt; Anne Hinds; Arjun Sharma; Markus Bosmann; Finn Hawkins; Eric J Burks; Mohsan Saeed; Andrew A Wilson; Elke Mühlberger; Darrell N Kotton

    doi:10.1101/2020.06.30.175695 Date: 2020-06-30

    ABSTRACTThe most severe and fatal infections MESHD with SARS-CoV-2 result in the acute respiratory distress HP syndrome MESHD, a clinical phenotype of coronavirus disease MESHD 2019 (COVID-19) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar epithelial type 2 cells (AT2s). Little is known about the initial responses of human lung alveoli to SARS-CoV-2 infection MESHD due in part to inability to access these cells from patients, particularly at early stages of disease MESHD. Here we present an in vitro human model that simulates the initial apical infection MESHD of the distal lung epithelium with SARS-CoV-2, using AT2s that have been adapted to air-liquid interface culture after their derivation from induced pluripotent stem cells (iAT2s). We find that SARS-CoV-2 induces a rapid global transcriptomic change in infected iAT2s characterized by a shift to an inflammatory phenotype predominated by the secretion of cytokines encoded by NF-kB target genes, delayed epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program. Over time, infected iAT2s exhibit cellular toxicity that can result in the death MESHD of these key alveolar facultative progenitors, as is observed in vivo in COVID-19 lung autopsies. Importantly, drug testing using iAT2s confirmed the efficacy of TMPRSS2 protease inhibition, validating putative mechanisms used for viral entry in human alveolar cells. Our model system reveals the cell-intrinsic responses of a key lung target cell to infection MESHD, providing a platform for further drug development and facilitating a deeper understanding of COVID-19 pathogenesis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    SARS-CoV-2 Spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

    Authors: Ganna Petruk; Manoj Puthia; Jitka Petrlova; Ann-Charlotte Strömdahl; Sven Kjellström; Artur Schmidtchen

    doi:10.1101/2020.06.29.175844 Date: 2020-06-29

    ABSTRACTThere is a well-known and established link between high lipopolysaccharide (LPS) levels in blood SERO and the metabolic syndrome MESHD (MS). MS is a risk factor for developing severe COVID-19 and acute respiratory distress HP syndrome MESHD (ARDS). Here we define an interaction between SARS-CoV-2 Spike (S) protein and LPS and its link to aggravated inflammation MESHD in vitro and in vivo. Electrophoresis under native conditions demonstrated that SARS-CoV-2 S protein binds to Escherichia coli LPS, forming high molecular weight aggregates. Microscale thermophoresis analysis further defined the interaction, having a KD of ~47 nM, similar to the observed affinity between LPS and the human receptor CD14. Moreover, S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) and cytokine responses in monocytic THP-1 cells and human blood SERO, respectively. In an experimental model of localized inflammation MESHD, employing NF-κB reporter mice and in vivo bioimaging, S protein in conjunction with LPS significantly increased the inflammatory response HP when compared with S protein and LPS alone. Apart from providing information on LPS as a ligand for S protein, our results are of relevance for studies on comorbidities involving bacterial endotoxins, such as the MS, or co-existing acute and chronic infections HP infections MESHD in COVID-19 patients.Competing Interest StatementA.S is a founder and shareholder of in2cure AB, a company developing therapies based on host defense peptides. A patent application related to the present work, with A.S. and G.P. listed as inventors, has been filed.AbbreviationsARDSacute respiratory distress HP syndromeCOVID-19coronavirus disease MESHD 2019MSmetabolic syndromeLBPLPS-binding proteinLPSlipopolysaccharideNF-κBnuclear factor-kappa BSARS-CoV-2 Spike proteinS proteinTLR4Toll-like receptor 4View Full Text

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MeSH Disease
Human Phenotype

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