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Article ; Online: Enoxaparin is associated with lower rates of mortality than unfractionated Heparin in hospitalized COVID-19 patients

Colin Pawlowski / AJ Venkatakrishnan / Christian Kirkup / Gabriela Berner / Arjun Puranik / John C. O'Horo / Andrew D. Badley / Venky Soundararajan

EClinicalMedicine, Vol 33, Iss , Pp 100774- (2021)

2021

Abstract: Background: Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences ...

Abstract	Background: Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. Methods: We analyzed records of 1,113 patients in the Mayo Clinic Electronic Health Record (EHR) database who were admitted to the hospital for COVID-19 between April 4, 2020 and August 31, 2020, including 19 different Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Among this patient population, we compared cohorts of patients who received different types of anticoagulants, including 441 patients who received unfractionated Heparin and 166 patients who received Enoxaparin. Clinical outcomes at 28 days were compared, and propensity score matching was used to control for potential confounding variables including: demographics, comorbidities, ICU status, chronic kidney disease stage, and oxygenation status. Patients with a history of acute kidney injury and patients who received multiple types of anticoagulants were excluded from the study. Findings: We find that COVID-19 patients administered unfractionated Heparin but not Enoxaparin have higher rates of 28-day mortality (risk ratio: 4.3; 95% Confidence Interval [C.I.].: [1.8, 10.2]; p-value: 8.5e−4, Benjamini Hochberg [BH] adjusted p-value: 2.1e−3), after controlling for potential confounding factors. Interpretation: This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by Enoxaparin versus unfractionated Heparin. Funding: This work was supported by Nference, inc.
Keywords	Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Casp8p41

Rahul Sampath / Nathan W. Cummins / Andrew D. Badley

Japanese Clinical Medicine, Vol

The Protean Mediator of Death in CD4 T-cells that Replicate HIV

2016 Volume 9

Abstract: HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient) set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, ...

Abstract	HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient) set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, which is thought to comprise CD4-positive cells that harbor integrated, replication-competent HIV provirus. These cells do not express viral proteins, are indistinguishable from uninfected CD4 cells, and are thought to be responsible for HIV viral rebound–-that occurs within weeks of combination anti retroviral therapy (cART) interruption. Modalities to engineer transcriptional stimulation (reactivation) of this dormant integrated HIV provirus, leading to expression of cytotoxic viral proteins, are thought to be a specific way to eradicate the latently infected CD4 pool and are becoming increasingly relevant in the era of HIV cure. HIV protease is one such protein produced after HIV reactivation that cleaves procaspase-8 to generate a novel protein Casp8p41. Casp8p41 then binds to the BH3 domain of BAK, leading to BAK oligomerization, mitochondrial depolarization, and apoptosis. In central memory T cells (TCMs) from HIV-infected patients, an elevated Bcl-2/procaspase-8 ratio was observed, and Casp8p41 binding to Bcl-2 was associated with a lack of reactivation-induced cell death. This was reversed by priming cells with a specific Bcl-2 antagonist prior to reactivation, resulting in increased cell death and decreased HIV DNA in a Casp8p41-dependent pathway. This review describes the biology, clinical relevance, and implications of Casp8p41 for a potential cure.
Keywords	Medicine (General) ; R5-920
Subject code	570
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Changing Landscape of Liver Transplantation in the Post-DAA and Contemporary ART Era

Huma Saeed / Edison J. Cano / Mohammad Qasim Khan / Zachary A. Yetmar / Byron Smith / Stacey A. Rizza / Andrew D. Badley / Maryam Mahmood / Michael D. Leise / Nathan W. Cummins

Life, Vol 12, Iss 1755, p

2022 Volume 1755

Abstract: Combination anti-retroviral therapy has drastically improved solid organ transplantation outcomes in persons living with HIV. DAA therapy has led to the successful eradication of HCV. While recent data have suggested improvement in outcomes in HIV/HCV- ... ...

Abstract	Combination anti-retroviral therapy has drastically improved solid organ transplantation outcomes in persons living with HIV. DAA therapy has led to the successful eradication of HCV. While recent data have suggested improvement in outcomes in HIV/HCV-coinfected liver transplant recipients, temporal trends in patient survival within pre- and post-DAA eras are yet to be elucidated. The UNOS database was utilized to identify deceased donor liver transplant recipients between 1 January 2000 and 30 September 2020 and stratify them by HIV and HCV infection status. A total of 85,730 patients met the inclusion criteria. One-year and five-year patient survival improved (93% and 80%, respectively) for all transplants performed post-2015. For HIV/HCV-coinfected recipients, survival improved significantly from 78% (pre-2015) to 92% (post-2015). Multivariate regression analyses identified advanced recipient age, Black race, diabetes mellitus and decompensated cirrhosis as risk factors associated with higher one-year mortality. Liver transplant outcomes in HIV/HCV-coinfected liver transplant recipients have significantly improved over the last quinquennium in the setting of the highly effective combination of ART and DAA therapy. The presence of HIV, HCV, HIV/HCV-coinfection and active HCV viremia at the time of transplant do not cause higher mortality risk in liver transplant recipients in the current era.
Keywords	liver transplantation ; hepatitis C virus ; HIV/AIDS ; direct-acting antiviral therapy ; anti-retroviral therapy ; Science ; Q
Subject code	610 ; 360
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Benchmarking evolutionary tinkering underlying human–viral molecular mimicry shows multiple host pulmonary–arterial peptides mimicked by SARS-CoV-2

A. J. Venkatakrishnan / Nikhil Kayal / Praveen Anand / Andrew D. Badley / George M. Church / Venky Soundararajan

Cell Death Discovery, Vol 6, Iss 1, Pp 1-

2020 Volume 14

Abstract: Abstract The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this ...

Abstract	Abstract The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral–human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B40:01, HLA-B40:02, and HLA-B35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human–viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Cytology ; QH573-671 ; covid19
Subject code	501
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pre-existing conditions are associated with COVID-19 patients’ hospitalization, despite confirmed clearance of SARS-CoV-2 virus

Colin Pawlowski / AJ Venkatakrishnan / Eshwan Ramudu / Christian Kirkup / Arjun Puranik / Nikhil Kayal / Gabriela Berner / Akash Anand / Rakesh Barve / John C. O'Horo / Andrew D. Badley / Venky Soundararajan

EClinicalMedicine, Vol 34, Iss , Pp 100793- (2021)

2021

Abstract: Background: Consecutive negative SARS-CoV-2 PCR test results are being considered to estimate viral clearance in COVID-19 patients. However, there are anecdotal reports of hospitalization from protracted COVID-19 complications despite such confirmed ... ...

Abstract	Background: Consecutive negative SARS-CoV-2 PCR test results are being considered to estimate viral clearance in COVID-19 patients. However, there are anecdotal reports of hospitalization from protracted COVID-19 complications despite such confirmed viral clearance, presenting a clinical conundrum. Methods: We conducted a retrospective analysis of 222 hospitalized COVID-19 patients to compare those that were readmitted post-viral clearance (hospitalized post-clearance cohort, n = 49) with those that were not re-admitted post-viral clearance (non-hospitalized post-clearance cohort, n = 173) between February and October 2020. In order to differentiate these two cohorts, we used neural network models for the ‘augmented curation’ of comorbidities and complications with positive sentiment in the Electronic Hosptial Records physician notes. Findings: In the year preceding COVID-19 onset, anemia (n = 13 [26.5%], p-value: 0.007), cardiac arrhythmias (n = 14 [28.6%], p-value: 0.015), and acute kidney injury (n = 7 [14.3%], p-value: 0.030) were significantly enriched in the physician notes of the hospitalized post-clearance cohort. Interpretation: Overall, this retrospective study highlights specific pre-existing conditions that are associated with higher hospitalization rates in COVID-19 patients despite viral clearance and motivates follow-up prospective research into the associated risk factors. Funding: This work was supported by Nference, inc.
Keywords	Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations

Colin Pawlowski / Arjun Puranik / Hari Bandi / A. J. Venkatakrishnan / Vineet Agarwal / Richard Kennedy / John C. O’Horo / Gregory J. Gores / Amy W. Williams / John Halamka / Andrew D. Badley / Venky Soundararajan

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 20

Abstract: Abstract Clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection through trained immunity. In this exploratory study, we analyze immunization records from 137,037 individuals who received SARS- ... ...

Abstract	Abstract Clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection through trained immunity. In this exploratory study, we analyze immunization records from 137,037 individuals who received SARS-CoV-2 PCR tests. We find that polio, Haemophilus influenzae type-B (HIB), measles-mumps-rubella (MMR), Varicella, pneumococcal conjugate (PCV13), Geriatric Flu, and hepatitis A/hepatitis B (HepA–HepB) vaccines administered in the past 1, 2, and 5 years are associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, comorbidities, and number of other vaccinations. Furthermore, age, race/ethnicity, and blood group stratified analyses reveal significantly lower SARS-CoV-2 rate among black individuals who have taken the PCV13 vaccine, with relative risk of 0.45 at the 5 year time horizon (n: 653, 95% CI (0.32, 0.64), p-value: 6.9e−05). Overall, this study identifies existing approved vaccines which can be promising candidates for pre-clinical research and Randomized Clinical Trials towards combating COVID-19.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Anemia during SARS-CoV-2 infection is associated with rehospitalization after viral clearance

Patrick J. Lenehan / Eshwan Ramudu / A.J. Venkatakrishnan / Gabriela Berner / Reid McMurry / John C. O'Horo / Andrew D. Badley / William Morice, II / John Halamka / Venky Soundararajan

iScience, Vol 24, Iss 7, Pp 102780- (2021)

2021

Abstract: Summary: Patients with COVID-19 can experience symptoms and complications after viral clearance. It is important to identify clinical features of patients who are likely to experience these prolonged effects. We conducted a retrospective study to compare ...

Abstract	Summary: Patients with COVID-19 can experience symptoms and complications after viral clearance. It is important to identify clinical features of patients who are likely to experience these prolonged effects. We conducted a retrospective study to compare longitudinal laboratory test measurements (hemoglobin, hematocrit, estimated glomerular filtration rate, serum creatinine, and blood urea nitrogen) in patients rehospitalized after PCR-confirmed SARS-CoV-2 clearance (n = 104) versus patients not rehospitalized after viral clearance (n = 278). Rehospitalized patients had lower median hemoglobin levels in the year prior to COVID-19 diagnosis (Cohen's D = −0.50; p = 1.2 × 10−3) and during their active SARS-CoV-2 infection (Cohen's D = −0.71; p = 4.6 × 10−8). Rehospitalized patients were also more likely to be diagnosed with moderate or severe anemia during their active infection (Odds Ratio = 4.07; p = 4.99 × 10−9). These findings suggest that anemia-related laboratory tests should be considered in risk stratification algorithms for patients with COVID-19.
Keywords	Virology ; Pathophysiology ; Science ; Q
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association Between Chronic Statin Use and 30-Day Mortality in Hospitalized Patients With COVID-19

Zachary A. Yetmar, MD / Douglas W. Challener, MD / Imad M. Tleyjeh, MD, MSc / M. Rizwan Sohail, MD / James R. Cerhan, MD, PhD / Andrew D. Badley, MD / John C. O’Horo, MD, MPH

Mayo Clinic Proceedings: Innovations, Quality & Outcomes, Vol 5, Iss 2, Pp 442-

2021 Volume 446

Abstract: Objective: To determine the association between chronic statin use and mortality in patients hospitalized with coronavirus disease 2019 (COVID-19). Patients and Methods: We identified a retrospective cohort of patients requiring admission at the Mayo ... ...

Abstract	Objective: To determine the association between chronic statin use and mortality in patients hospitalized with coronavirus disease 2019 (COVID-19). Patients and Methods: We identified a retrospective cohort of patients requiring admission at the Mayo Clinic using our enterprise-wide COVID-19 registry from March 1, 2020, through September 30, 2020. Available information included age, sex, use of statins, medical comorbidities, and 30-day mortality. We estimated the association of statins with 30-day mortality using odds ratios and 95% CIs from logistic regression modeling. Results: Patients (N=1295) between the ages of 30 and 80 years tested positive for COVID-19 and required admission during the study period, of whom 500 (38.6%) were taking statins at admission. Patients taking statins were older and more likely to have diabetes mellitus or congestive heart failure. Within 30 days of diagnosis, 59 (4.6%) died. In multivariable analysis, statin users did not have statistically different odds of death within 30 days with an odds ratio of 1.14 (95% CI, 0.64 to 2.03; P=.67) compared to nonusers. Conclusion: Patients with COVID-19 taking statins had similar 30-day mortality to those not taking statins after adjusting for relevant covariates. Although this is partly influenced by a higher prevalence of risk factors for more severe COVID-19 presentation not entirely adjusted for by the Charlson comorbidity index, these data would not support statins as a likely therapeutic intervention for COVID-19 in the hospital setting.
Keywords	Medicine (General) ; R5-920
Subject code	310
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in patients with severe COVID-19

Xiaosheng Wu / Michelle K. Manske / Gordon J. Ruan / Taylor L. Witter / Kevin E. Nowakowski / Jithma P. Abeykoon / Xinyi Tang / Yue Yu / Kimberly A. Gwin / Annie Wu / Vanessa Taupin / Vaishali Bhardwaj / Jonas Paludo / Surendra Dasari / Haidong Dong / Stephen M. Ansell / Andrew D. Badley / Matthew J. Schellenberg / Thomas E. Witzig

iScience, Vol 26, Iss 6, Pp 106929- (2023)

2023

Abstract: Summary: Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus- ... ...

Abstract	Summary: Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+ monocytes to induce inflammasomal cytokine/chemokine responses including IL1β, IL8, and CCL2. Levels of ORF8 protein in the blood correlate with severity and disease-specific mortality in patients with acute SARS-CoV-2 infection. Furthermore, the ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro. Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment strategy for severe COVID-19.
Keywords	Immunity ; Virology ; Science ; Q
Subject code	616 ; 610
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Reactivating latent HIV with PKC agonists induces resistance to apoptosis and is associated with phosphorylation and activation of BCL2.

Andrea J French / Sekar Natesampillai / Ashton Krogman / Cristina Correia / Kevin L Peterson / Alecia Alto / Aswath P Chandrasekar / Anisha Misra / Ying Li / Scott H Kaufmann / Andrew D Badley / Nathan W Cummins

PLoS Pathogens, Vol 16, Iss 10, p e

2020 Volume 1008906

Abstract: Eradication of HIV-1 by the "kick and kill" strategy requires reactivation of latent virus to cause death of infected cells by either HIV-induced or immune-mediated apoptosis. To date this strategy has been unsuccessful, possibly due to insufficient cell ...

Abstract	Eradication of HIV-1 by the "kick and kill" strategy requires reactivation of latent virus to cause death of infected cells by either HIV-induced or immune-mediated apoptosis. To date this strategy has been unsuccessful, possibly due to insufficient cell death in reactivated cells to effectively reduce HIV-1 reservoir size. As a possible cause for this cell death resistance, we examined whether leading latency reversal agents (LRAs) affected apoptosis sensitivity of CD4 T cells. Multiple LRAs of different classes inhibited apoptosis in CD4 T cells. Protein kinase C (PKC) agonists bryostatin-1 and prostratin induced phosphorylation and enhanced neutralizing capability of the anti-apoptotic protein BCL2 in a PKC-dependent manner, leading to resistance to apoptosis induced by both intrinsic and extrinsic death stimuli. Furthermore, HIV-1 producing CD4 T cells expressed more BCL2 than uninfected cells, both in vivo and after ex vivo reactivation. Therefore, activation of BCL2 likely contributes to HIV-1 persistence after latency reversal with PKC agonists. The effects of LRAs on apoptosis sensitivity should be considered in designing HIV cure strategies predicated upon the "kick and kill" paradigm.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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