BACKGROUND COVID-19 convalescent plasma (CCP) viral specific antibody levels that translate into recipient post-transfusion antibody levels sufficient to prevent disease progression is not defined. METHODS This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low post-transfusion antibody levels was established by two methods: 1) analyzing virus neutralization-equivalent anti-Spike-receptor-binding-domain immunoglobulin G (anti-S-RBD IgG) responses in donors or 2) receiver operated curve (ROC) analysis. RESULTS SARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3 fold into post-transfusion seronegative recipients from matched donor units. Viral specific antibody delivered approximated 1.2 mg. The high antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma) with antibody cutoffs established by both methods-donor-based virus neutralization cutoff in post-transfusion recipients: (0/85; 0% versus 15/276; 5.6%) p=0.03 or ROC based cutoff: (0/94; 0% versus 15/267; 5.4%) p=0.01. CONCLUSION In unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use. Trial registration: NCT04373460 FUNDING Defense Health Agency and others.
Han-Sol Park, Anna Yin, Caelan Barranta, John S. Lee, Christopher A. Caputo, Jaiprasath Sachithanandham, Maggie Li, Steve Yoon, Ioannis Sitaras, Anne Jedlicka, Yolanda Eby, Malathi Ram, Reinaldo E. Fernandez, Owen R. Baker, Aarthi G. Shenoy, Giselle S. Mosnaim, Yuriko Fukuta, Bela Patel, Sonya L. Heath, Adam C. Levine, Barry R. Meisenberg, Emily S. Spivak, Shweta Anjan, Moises A. Huaman, Janis E. Blair, Judith S. Currier, James H. Paxton, Jonathan M. Gerber, Joann R. Petrini, Patrick B. Broderick, William Rausch, Marie Elena Cordisco, Jean Hammel, Benjamin Greenblatt, Valerie C. Cluzet, Daniel Cruser, Kevin Oei, Matthew Abinante, Laura L. Hammitt, Catherine G. Sutcliffe, Donald N. Forthal, Martin S. Zand, Edward R. Cachay, Jay S. Raval, Seble G. Kassaye, Christi E. Marshall, Anusha Yarava, Karen Lane, Nichol A. McBee, Amy L. Gawad, Nicky Karlen, Atika Singh, Daniel E. Ford, Douglas A. Jabs, Lawrence J. Appel, David M. Shade, Bryan Lau, Stephan Ehrhardt, Sheriza N. Baksh, Janna R. Shapiro, Jiangda Ou, Yu Bin Na, Maria D. Knoll, Elysse Ornelas-Gatdula, Netzahualcóyotl Arroyo-Currás, Thomas J. Gniadek, Patrizio Caturegli, Jinke Wu, Nelson Ndahiro, Michael J. Betenbaugh, Alyssa Ziman, Daniel F. Hanley, Arturo Casadevall, Shmuel Shoham, Evan M. Bloch, Kelly A. Gebo, Aaron A.R. Tobian, Oliver Laeyendecker, Andrew Pekosz, Sabra L. Klein, David J. Sullivan
BACKGROUND While the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODS Eight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTS Maximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSION These findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDING NIH R01 AR071263.
Terence E. Ryan, Maria J. Torres, Chien-Te Lin, Angela H. Clark, Patricia M. Brophy, Cheryl A. Smith, Cody D. Smith, E. Matthew Morris, John P. Thyfault, P. Darrell Neufer
BACKGROUND Identifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODS We performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTS Compared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre–treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSION The results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATION ClinicalTrials.gov NCT03001128FUNDING NIH National Institute of Allergy and Infectious Diseases, Merck
Jonathan Z. Li, Meghan Melberg, Autumn Kittilson, Mohamed Abdel-Mohsen, Yijia Li, Evgenia Aga, Ronald J. Bosch, Elizabeth R. Wonderlich, Jennifer Kinslow, Leila B. Giron, Clara Di Germanio, Mark Pilkinton, Lynsay MacLaren, Michael Keefer, Lawrence Fox, Liz Barr, Edward Acosta, Jintanat Ananworanich, Robert Coombs, John Mellors, Steven Deeks, Rajesh T. Gandhi, Michael Busch, Alan Landay, Bernard Macatangay, Davey M. Smith, for the AIDS Clinical Trials Group A5345 Study Team
BACKGROUND. T cell responses are impaired in Staphylococcus aureus-infected children, highlighting a potential mechanism of immune evasion. This study tested the hypotheses that toxin-specific antibodies protect immune cells from bacterial killing and are associated with improved T cell function following infection. METHODS.S. aureus-infected and healthy children (n = 33 each) were prospectively enrolled. During acute infection and convalescence, we quantified toxin-specific IgG levels by ELISA, antibody function using a cell-killing assay, and functional T cell responses by ELISpot. RESULTS. There were no differences in toxin-specific IgG levels or ability to neutralize toxin-mediated immune cell killing between healthy and acutely-infected children, but antibody levels and function increased following infection. Similarly, T cell function, which was impaired during acute infection, improved following infection. However, the response to infection was highly variable; up to half of children did not have improved antibody or T cell function. Serum from children with higher ɑ-hemolysin (Hla)-specific IgG levels more strongly protected immune cells against toxin-mediated killing. Importantly, children whose serum more strongly protected against toxin-mediated killing also had stronger immune responses to infection, characterized by more elicited antibody and greater improvement in T cell function following infection. CONCLUSIONS. This study demonstrates that, despite T cell impairment during acute infection, S. aureus elicits toxin-neutralizing antibodies. Individual antibody responses and T cell recovery are variable. These findings also suggest that toxin-neutralizing antibodies protect antigen-presenting cells and T cells, thereby promoting immune recovery. Finally, failure to elicit toxin-neutralizing antibodies may identify children at risk for prolonged T cell suppression. FUNDING. NIAID R01AI125489 and Nationwide Children’s Hospital.
Maureen Kleinhenz, Zhaotao Li, Usha V. Chidella, Walissa Picard, Amber Wolfe, Jill Popelka, Robin Alexander, Christopher P. Montgomery
BACKGROUND. Obesity is a multi-factorial disease with adverse health implications including insulin resistance (IR). In patients with obesity, the presence of high circulating levels of leptin, deemed hyperleptinemia, is associated with IR. Recent data in mice with diet-induced-obesity (DIO) shows a partial reduction in leptin levels improves IR. Additional animal studies demonstrate IL-4 decreases leptin levels. In rodents, resident adipose tissue (AT) eosinophils (EOS) are the main source of IL-4 and are instrumental in maintaining metabolic homeostasis. A marked reduction in AT-EOS content is observed in animal models of DIO. These observations have not been explored in humans. METHODS. We analyzed AT from individuals with obesity and age-matched lean counterparts for AT-EOS content, IL-4, circulating leptin levels and measures of IR. RESULTS. Our results showed that individuals with obesity (n=15) had a significant reduction in AT-EOS content (P<0.01), decreased AT-IL-4 gene expression (P=0.02), and decreased IL-4 plasma levels (P<0.05) in addition to expected IR (P<0.001) and hyperleptinemia (P<0.01) compared to lean subjects (n=15). AT-EOS content inversely correlated with BMI (P=0.002) and IR (P=0.005). Ex vivo AT explants and in vitro cell culture of primary, human mature adipocytes exposed to either IL-4 or EOS conditioned media produced less leptin (P<0.05). CONCLUSIONS. Our results suggested for IL-4 to act as a link between EOS, AT, and leptin production. Future studies exploring this interaction may identify a new avenue for the treatment of obesity and its complications through amelioration of hyperleptinemia. TRIAL REGISTRATION. Clinicaltrials.gov NCT02378077 & NCT04234295. FUNDING. Dr. Eleanna De Filippis received support by Arizona Department of Health Services, Arizona Biomedical Research Commission (ABRC) (ADHS14-00003606), the Katryn H. and Roger Penske Career Development Award in Endocrinology in Honor of Dr. Ian Hay, and Mayo Foundation, KL2 TR002379-02-01 CTSA UL1 TR002377 NCATS/NIH. Dr. Elizabeth A. Jacobsen received support from NIAID AI132840 and Mayo Foundation
James D. Hernandez, Ting Li, Hamza Ghannam, Cassandra M. Rau, Mia Y. Masuda, James A. Madura, Elizabeth A. Jacobsen, Eleanna De Filippis
BACKGROUND. Information about the size, airway location, and longitudinal behavior of mucus plugs in asthma is needed to understand their role in mechanisms of airflow obstruction and to rationally design muco-active treatments. METHODS. Computed tomography (CT) lung scans from 57 asthma patients were analyzed to quantify mucus plug size and airway location, and paired CT scans obtained 3 years apart were analyzed to determine plug behavior over time. Radiologist annotations of mucus plugs were incorporated in an image-processing pipeline to generate size and location information that was related to measures of airflow. RESULTS. The length distribution of 778 annotated mucus plugs was multimodal and a 12 mm length defined short (“stubby”, ≤12 mm) and long (“stringy”, >12 mm) plug phenotypes. High mucus plug burden was disproportionately attributable to stringy mucus plugs. Mucus plugs localized predominantly to airway generations 6 to 9, and 47% of plugs in baseline scans, persisted in the same airway for three years, and fluctuated in length and volume. Mucus plugs in larger proximal generations had greater effects on spirometry measures than plugs in smaller distal generations, and a model of airflow that estimates the increased airway resistance attributable to plugs predicted higher impact for proximal and more numerous mucus plugs. CONCLUSIONS. Persistent mucus plugs in proximal airway generations occur in asthma and demonstrate a stochastic process of formation and resolution over time. Proximal airway mucus plugs are consequential for airflow and are in locations amenable to treatment by inhaled muco-active drugs or bronchoscopy. TRIAL REGISTRATION. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915 FUNDING. NIH Grants: R01 HL080414, UG1 HL139106, P01 HL107202, U01 HL146002, U10 HL109172, U10 HL109168, U10 HL109152, U10 HL109257, U10 HL109146, U10 HL109250, U10 HL109164, U10 109086, and T32 HL007185, F32 HL162422. The following companies provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi–Genzyme– Regeneron, and TEVA. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.
Brendan K. Huang, Brett M. Elicker, Travis S. Henry, Kimberly G. Kallianos, Lewis D. Hahn, Monica Tang, Franklin Heng, Charles E. McCulloch, Nirav R. Bhakta, Sharmila Majumdar, Jiwoong Choi, Loren C. Denlinger, Sean B. Fain, Annette T. Hastie, Eric A. Hoffman, Elliot Israel, Nizar N. Jarjour, Bruce D. Levy, David T. Mauger, Kaharu Sumino, Sally E. Wenzel, Mario Castro, Prescott G. Woodruff, John V. Fahy
BACKGROUND. Sepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients has generally relied on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision. METHODS. An ex vivo whole blood enzyme-linked immunosorbent (ELISpot) assay for cellular production of interferon-γ (IFN-γ) was evaluated in 107 septic and 68 non-septic patients from five academic health centers using blood samples collected on days 1, 4 and 7 following ICU admission. RESULTS. Compared with 46 healthy subjects, unstimulated and stimulated whole blood IFNγ expression were either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole blood IFNγ expression was significantly reduced on ICU days 1, 4 and 7 (all p<0.05), due to both significant reductions in total number of IFNγ producing cells and amount of IFNγ produced per cell (all p<0.05). Importantly, IFNγ total expression on day 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6 and procalcitonin. Septic patients with low IFNγ expression were older and had lower ALC and higher sPD-L1 and IL-10 concentrations, consistent with an immune suppressed endotype. CONCLUSIONS. A whole blood IFNγ ELISpot assay can both identify septic patients at increased risk of late mortality, and identify immune-suppressed, sepsis patients.
Evan L. Barrios, Monty B. Mazer, Patrick W. McGonagill, Christian B. Bergmann, Michael D. Goodman, Robert W. Gould, Mahil Rao, Valerie E. Polcz, Ruth Davis, Drew Del Toro, Marvin Dirain, Alexandra Dram, Lucas Hale, Mohammad Heidarian, Caleb Y. Kim, Tamara A. Kucaba, Jennifer P. Lanz, Ashley McCray, Alexandra Meszaros, Sydney M. Miles, Candace Nelson, Ivanna Rocha, Elvia E. Silva, Ricardo Ungaro, Andrew Walton, Julie Xu, Leilani Zeumer-Spataro, Anne M. Drewry, Muxuan Liang, Letita E. Bible, Tyler J. Loftus, Isaiah R. Turnbull, Philip A. Efron, Kenneth E. Remy, Scott C. Brakenridge, Vladimir P. Badovinac, Thomas S. Griffith, Lyle L. Moldawer, Richard S. Hotchkiss, Charles C. Caldwell
BACKGROUND Intrathecal injection is an attractive route through which drugs can be administered and directed to the spinal cord, restricted by the blood-spinal cord barrier. However, in vivo data on the distribution of cerebrospinal fluid (CSF) substances in the human spinal cord are lacking. We conducted this study to assess the enrichment of a CSF tracer in the upper cervical spinal cord and the brain stem.METHODS After lumbar intrathecal injection of a magnetic resonance imaging (MRI) contrast agent, gadobutrol, repeated blood samples and MRI of the upper cervical spinal cord, brain stem, and adjacent subarachnoid spaces (SAS) were obtained through 48 hours. The MRI scans were then analyzed for tracer distribution in the different regions and correlated to age, disease, and amounts of tracer in the blood to determine CSF-to-blood clearance.RESULTS The study included 26 reference individuals and 35 patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH). The tracer enriched all analyzed regions. Moreover, tracer enrichment in parenchyma was associated with tracer enrichment in the adjacent SAS and with CSF-to-blood clearance. Clearance from the CSF was delayed in patients with iNPH compared with younger reference patients.CONCLUSION A CSF tracer substance administered to the lumbar thecal sac can access the parenchyma of the upper cervical spinal cord and brain stem. Since CSF-to-blood clearance is highly individual and is associated with tracer level in CSF, clearance assessment may be used to tailor intrathecal treatment regimes.FUNDING South-Eastern Norway Regional Health and Østfold Hospital Trust supported the research and publication of this work.
Erik Melin, Are Hugo Pripp, Per Kristian Eide, Geir Ringstad
BACKGROUND Alcohol use disorder has a detrimental impact on global health and new treatment targets are needed. Preclinical studies show attenuating effects of glucagon-like peptide-1 (GLP-1) agonists on addiction-related behaviors in rodents and nonhuman primates. Some trials have shown an effect of GLP-1 agonism on reward processes in humans; however, results from clinical studies remain inconclusive.METHODS This is a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation. The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. The effect of dulaglutide on alcohol consumption was analyzed using a multivariable generalized linear model.RESULTS In the primary analysis, participants out of the cohort (n = 255) who reported drinking alcohol at baseline and who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide n = 76) were included. The median age was 42 (IQR 33–53) with 61% (n = 92) females. At week 12, participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52–0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.CONCLUSION These results provide evidence that dulaglutide reduces alcohol intake in humans and contribute to the growing body of literature promoting the use of GLP-1 agonists in treatment of substance use disorders.TRIAL REGISTRATION ClinicalTrials.gov NCT03204396.FUNDING Swiss National Foundation, Gottfried Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Hemmi Foundation, University of Basel, University Hospital Basel, Swiss Academy of Medical Science.
Leila Probst, Sophie Monnerat, Deborah R. Vogt, Sophia Lengsfeld, Thilo Burkard, Andrea Meienberg, Cemile Bathelt, Mirjam Christ-Crain, Bettina Winzeler
BACKGROUND Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODS This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTS Seventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSION The unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDING US National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.
Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L. McAtee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C. Peckham-Gregory, Razia Moorad, Carrie L. Kovarik, Liane R. Campbell, Parth S. Mehta, Peter N. Kazembe, Carl E. Allen, Michael E. Scheurer, Nmazuo W. Ozuah, Dirk P. Dittmer, Nader Kim El-Mallawany
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