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  • 1
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 13, No. 612 ( 2021-09-22)
    Abstract: Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN–specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non–COVID-19 controls revealed a lack of type I IFN–stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN–specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN–specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Elsevier BV ; 2022
    In:  Journal of Mass Spectrometry and Advances in the Clinical Lab Vol. 23 ( 2022-01), p. 50-57
    In: Journal of Mass Spectrometry and Advances in the Clinical Lab, Elsevier BV, Vol. 23 ( 2022-01), p. 50-57
    Type of Medium: Online Resource
    ISSN: 2667-145X
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 3058462-0
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  • 3
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2022
    In:  Journal of Analytical Toxicology Vol. 46, No. 3 ( 2022-03-21), p. 303-321
    In: Journal of Analytical Toxicology, Oxford University Press (OUP), Vol. 46, No. 3 ( 2022-03-21), p. 303-321
    Abstract: Many natural products have biological effects on humans and animals. Poisoning caused by natural products is common in clinical toxicology cases. Liquid chromatography–high-resolution mass spectrometry (LC–HRMS) has recently emerged as a powerful analytical tool for large-scale target screening, and the application of LC–HRMS can be expanded to evaluate potential natural product poisoning in clinical cases. We report the construction of an LC–HRMS spectral library of 95 natural products commonly implicated in poisoning, and an LC–HRMS assay was validated for definitive detection of natural products in urine and serum samples. For each compound, the limit of detection was determined in the analytical range of 1.0–1,000 ng/mL for urine samples and 0.50–500 ng/mL for serum samples. The mean (SD) values of matrix effects for urine samples and that for serum samples were both −21% (22%), and the mean (SD) value of recovery for serum samples was 89% (26%). The LC–HRMS assay was successfully applied to identify natural products in clinical cases. The spectral library parameters of each compound are provided in the supplementary material to aid other laboratories in identification of unknown natural toxins and development of similar methods on different mass spectrometry platforms.
    Type of Medium: Online Resource
    ISSN: 0146-4760 , 1945-2403
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2010848-5
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  • 4
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2021
    In:  The Journal of Applied Laboratory Medicine Vol. 6, No. 3 ( 2021-04-29), p. 592-605
    In: The Journal of Applied Laboratory Medicine, Oxford University Press (OUP), Vol. 6, No. 3 ( 2021-04-29), p. 592-605
    Abstract: As modulators of nitric oxide generation, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) may play important roles in sepsis. Current data on dimethylarginines are conflicting, and direct comparison data with other biomarkers are limited. Methods Fifty-five patients were included in the final analysis and were divided into 4 groups: infection without sepsis, sepsis, severe sepsis, and septic shock. The first available samples on hospital admission were analyzed for ADMA, SDMA, procalcitonin (PCT), C-reactive protein, heparin binding protein (HBP), zonulin, soluble CD25 (sCD25), and soluble CD163 (sCD163). White blood cell (WBC) counts and lactate results were obtained from the medical record. Results There were no statistically significant differences in ADMA and SDMA concentrations among the 4 groups; however, PCT, WBC, HBP, and sCD25 showed statistically significant differences. Lactate only trended toward statistical significance, likely because of limited availability in the medical record. Differences between survivors of sepsis and nonsurvivors at 30 days were highly statistically significant for ADMA and SDMA. Areas under the curve (AUCs) for ROC analysis were 0.88 and 0.95, respectively. There was also a statistically significant difference between survivors of sepsis and nonsurvivors for HBP, lactate, sCD25, and sCD163; however, AUCs for ROC curves were not statistically significantly different from 0.5. Conclusions Analysis of biomarkers other than dimethylarginines were in general agreement with expectations from the literature. ADMA and SDMA may not be specific markers for diagnosis of sepsis; however, they may be useful in short-term mortality risk assessment.
    Type of Medium: Online Resource
    ISSN: 2576-9456 , 2475-7241
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 5
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2021
    In:  Clinical Infectious Diseases Vol. 73, No. 9 ( 2021-11-02), p. e3095-e3097
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 73, No. 9 ( 2021-11-02), p. e3095-e3097
    Abstract: The kinetics of IgG avidity maturation during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was studied. The IgG avidity assay, using a novel label-free immunoassay technology, revealed a strong correlation between IgG avidity and days since symptom onset. Peak readings were significantly higher in severe than mild disease cases.
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2002229-3
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  • 6
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 8, No. 8 ( 2021-08-01)
    Abstract: We report a patient with connective tissue disease who developed modest severe acute respiratory syndrome coronavirus 2 receptor binding domain–specific antibody levels and a lack of neutralization capacity, despite having received 3 mRNA coronavirus disease 2019 vaccines and holding anti-B-cell therapy for  & gt;7 months before vaccination. The patient developed virus-specific T-cell responses.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2757767-3
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  • 7
    In: Journal of Clinical Microbiology, American Society for Microbiology, Vol. 59, No. 7 ( 2021-06-18)
    Abstract: Methods designed to measure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) humoral response include virus neutralization tests to determine antibody neutralization activity. For ease of use and universal applicability, surrogate virus neutralization tests (sVNTs) based on antibody-mediated blockage of molecular interactions have been proposed. A surrogate virus neutralization test was established on a label-free immunoassay platform (LF-sVNT). The LF-sVNT analyzes the binding ability of SARS-CoV-2 spike protein receptor-binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) after neutralizing RBD with antibodies in serum. The LF-sVNT neutralizing antibody titers (50% inhibitory concentration [IC 50 ]) were determined from serum samples ( n  = 246) from coronavirus disease 2019 (COVID-19) patients ( n  = 113), as well as the IgG concentrations and the IgG avidity indices. Although there was variability in the kinetics of the IgG concentrations and neutralizing antibody titers between individuals, there was an initial rise, plateau, and then in some cases a gradual decline at later time points after 40 days after symptom onset. The IgG avidity indices, in the same cases, plateaued after an initial rise and did not show a decline. The LF-sVNT can be a valuable tool in research and clinical laboratories for the assessment of the presence of neutralizing antibodies to COVID-19. This study is the first to provide longitudinal neutralizing antibody titers beyond 200 days post-symptom onset. Despite the decline of IgG concentration and neutralizing antibody titer, IgG avidity index increases, reaches a plateau, and then remains constant up to 8 months postinfection. The decline of antibody neutralization activity can be attributed to the reduction in antibody quantity rather than the deterioration of antibody quality, as measured by antibody avidity.
    Type of Medium: Online Resource
    ISSN: 0095-1137 , 1098-660X
    RVK:
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2021
    detail.hit.zdb_id: 1498353-9
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2022
    In:  The Journal of Applied Laboratory Medicine Vol. 7, No. 2 ( 2022-03-02), p. 625-627
    In: The Journal of Applied Laboratory Medicine, Oxford University Press (OUP), Vol. 7, No. 2 ( 2022-03-02), p. 625-627
    Type of Medium: Online Resource
    ISSN: 2576-9456 , 2475-7241
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2021
    In:  Open Forum Infectious Diseases Vol. 8, No. Supplement_1 ( 2021-12-04), p. S805-S805
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 8, No. Supplement_1 ( 2021-12-04), p. S805-S805
    Abstract: Limited data are available on whether there are differences in the immune response to SARS-CoV-2 vaccination by HIV status or by mRNA vaccine type. Methods We saved residual outpatient laboratory samples of all previously mRNA-vaccinated individuals in the adult medicine clinics of a public hospital with a large outpatient HIV clinic during May 2021, and then excluded individuals with prior SARS-CoV-2 infection. We next 1:1 matched 100 PLWH to 100 outpatient HIV-negative adult medicine patients receiving care for chronic medical conditions on days since completion of second vaccination (minimum 10), sex, age +/-5 years, and the type of mRNA vaccine received. We defined a non-response as reciprocal pseudovirus neutralizing titer & lt; 10 and anti-RBD IgG & lt; 10 relative fluorescent units, and compared non-response by HIV status using mixed models. Results In each matched group there were 13 women; 25 received the mRNA-1273 vaccine and 75 received the BNT162b2 vaccine; the median age was 59. The median time from second vaccination was 35 days (IQR: 20–63). Among PLWH, the median CD4+ T-cell count was 511 (IQR: 351–796) and 5 individuals had HIV RNA & gt; 200. We found 2.4-fold greater odds of pseudovirus neutralizing antibody non-response among PLWH compared to people without HIV (95% CI=1.1–5.4). Although few individuals in each group did not mount an IgG response (12 among PLWH vs. 5; p=0.08), continuous anti-RBD IgG concentrations were 43% lower among PLWH (95% CI=0.36–0.88). Among PLWH, when adjusting for age, sex, and days post-vaccination, each 100-cell increase in CD4+T-cell count was associated with 22% higher neutralizing antibody titers (GMR 1.22; 95% CI=1.09–1.37). Unsuppressed HIV RNA & gt;200 was associated with 89% lower neutralizing antibody titers (GMR 0.11; 95% CI=0.01–0.84). Receipt of the BNT162b2 vs. mRNA-1273 vaccine was associated with 77% lower neutralizing titers (GMR 0.23; 95% CI=0.08–0.65) among PLWH. Post-mRNA Vaccination SARS-CoV-2 IgG Concentrations and Pseudovirus Neutralizing Titers by HIV Status and Vaccine Conclusion PLWH had lower than expected response to mRNA SARS-CoV-2 vaccines, with the highest non-response among those with low CD4+ counts, unsuppressed HIV RNA, and those who received the BNT162b2 vaccine. Immunization strategies to improve immune responses among PLWH should be studied, and may include booster vaccination or preference of the mRNA-1273 vaccine in this group. Disclosures Matthew A. Spinelli, MD, MAS, Nothing to disclose Monica Gandhi, MD, MPH, Nothing to disclose
    Type of Medium: Online Resource
    ISSN: 2328-8957
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2757767-3
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  • 10
    In: Current Drug Metabolism, Bentham Science Publishers Ltd., Vol. 24 ( 2023-04-18)
    Abstract: Therapeutic antisense oligonucleotides (ASOs) represent a diverse array of chemically modified singlestranded deoxyribonucleotides that work complementarily to affect their mRNA targets. They vastly differ from conventional small molecules. These newly developed therapeutic ASOs possess unique absorption, distribution, metabolism, and excretion (ADME) processes that ultimately determine their pharmacokinetic, efficacy and safety profiles. The ADME properties of ASOs and associated key factors have not been fully investigated. Therefore, thorough characterization and in-depth study of their ADME properties are critical to support drug discovery and development processes for safe and effective therapeutic ASOs. In this review, we discussed the main factors affecting the ADME characteristics of these novels and evolving therapies. The major changes to ASO backbone and sugar chemistry, conjugation approaches, sites and routes of administration, etc., are the principal determinants of ADME and PK profiles that consequentially impact their efficacy and safety profiles. In addition, species difference and DDI considerations are important in understanding ADME profile and PK translatability but are less studied for ASOs. We, therefore, have summarized these aspects based on current knowledge and provided discussions in this review. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of ASO drugs and provide future perspectives and knowledge gap analysis.
    Type of Medium: Online Resource
    ISSN: 1389-2002
    Language: English
    Publisher: Bentham Science Publishers Ltd.
    Publication Date: 2023
    SSG: 15,3
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