Publications

Upinder Singh
Upinder Singh
Stanford Medicine Professor of Infectious Disease and Professor of Medicine (Infectious Diseases & Geographic Medicine), Emerita
usingh@stanford.edu

Publications

  • Long COVID trajectories in the prospectively followed RECOVER-Adult US cohort. Nature communications Thaweethai, T., Donohue, S. E., Martin, J. N., Hornig, M., Mosier, J. M., Shinnick, D. J., Ashktorab, H., Atieh, O., Blomkalns, A., Brim, H., Chen, Y., Cortez, M. M., Erdmann, N. B., Flaherman, V., Goepfert, P., Goldman, J. D., Hamburg, N. M., Han, J. E., Heath, J. R., Jacoby, V., Jolley, S. E., Kelly, J. D., Kelly, S. W., Kim, C., Krishnan, J. A., Letts, R., Levitan, E. B., Modes, M. E., McComsey, G. A., Metz, T. D., Mullington, J. M., Ofotokun, I., Okumura, M. J., Paredes, C. C., Patterson, T. F., Peluso, M. J., Reece, R., Sherif, Z. A., Simhan, H. N., Simmons, C., Singh, U., Taylor, B. S., Taylor, B. D., Trinity, J. D., Troxel, A. B., Utz, P. J., Vasey, A. J., Weinberger, E., Wiley, Z., Wisnivesky, J., Yee, L. M., Horwitz, L., Foulkes, A. S., Levy, B. D. 2025; 16 (1): 9557

    Abstract

    Longitudinal trajectories of Long COVID remain ill-defined, yet are critically needed to advance clinical trials, patient care, and public health initiatives for millions of individuals with this condition. Long COVID trajectories were determined prospectively among 3,659 participants (69% female; 99.6% Omicron era) in the National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) Adult Cohort. Finite mixture modeling was used to identify distinct longitudinal profiles based on a Long COVID research index measured 3 to 15 months after infection. Eight longitudinal profiles were identified. Overall, 195 (5%) had persistently high Long COVID symptom burden, 443 (12%) had non-resolving, intermittently high symptom burden, and 526 (14%) did not meet criteria for Long COVID at 3 months but had increasing symptoms by 15 months, suggestive of distinct pathophysiologic features. At 3 months, 377 (10%) met the research index threshold for Long COVID. Of these, 175 (46%) had persistent Long COVID, 132 (35%) had moderate symptoms, and 70 (19%) appeared to recover. Identification of these Long COVID symptom trajectories is critically important for targeting enrollment for future studies of pathophysiologic mechanisms, preventive strategies, clinical trials and treatments.

    View details for DOI 10.1038/s41467-025-65239-4

    View details for PubMedID 41249167

    View details for PubMedCentralID 10415000

  • Evaluation of Interventions for Cognitive Symptoms in Long COVID: A Randomized Clinical Trial. JAMA neurology Knopman, D. S., Koltai, D., Laskowitz, D., Becker, J., Charvet, L., Wisnivesky, J., Federman, A., Silverstein, A., Lokhnygina, Y., Pilloni, G., Haddad, M., Mahncke, H., Van Vleet, T., Huang, R., Cox, W., Terry, D., Karwowski, J., McCray, N., Lin, J. J., McComsey, G. A., Singh, U., Geng, L. N., Chu, H. Y., Reece, R., Moy, J., Arvanitakis, Z., Parthasarathy, S., Patterson, T. F., Gupta, A., Ostrosky-Zeichner, L., Parsonnet, J., Kiriakopoulos, E. T., Fong, T. G., Mullington, J., Jolley, S., Shah, N. S., Morimoto, S. S., Lee-Iannotti, J. K., Killgore, W. D., Dwyer, B., Stringer, W., Isache, C., Frontera, J. A., Krishnan, J. A., O'Steen, A., James, M., Harper, B. L., Zimmerman, K. O., RECOVER-NEURO Clinical Trial Group, Lawler, A., Johnson, B., Pitsch, C., Feuerriegel, E., McKeehan, J., Molden, J., Reid, K., Erlandson, K., Dowling, S., Wodushek, T., Canton, D., Turut, D., Sheppard, E., Scott-Sutherland, J., Hauser, K., Shaughnessy, L., Doyle, M., Beck, M., Heisey, S., Katragadda, V., Yusuff, A., Perlack, A., Tran, A., Dwyer, B., Altaras, C., Merisme, C., Krause, D., Schulte, D., Dupre, F., Sanchez, G., Krengel, M., Ly, M., Asupoto, O., Simmons, Q., Schroeder, R., Timlin, S., Devis, Y., Carter, D., Caceres, L., Rodriguez, M., Alvarez, Z., Yakubov, A., Engelson, C., Reyes, M., Youkhana, A., Jennings, C., Gonzalez, D., Naquiallah, D., Behun, D., Stephen, E., Timm, E., Bilimoria, F., Li, G., Stricker, J., Torres, J., Garcia, M., Thomas, M., Kang, M., Suarez, R., Carmona, T., Ramirez, A., Kadubek, G., Baker, A., Romo-Serna, A., Predki, B., Leman, C., Panhans, C., Roth, G., Rudraraju, G., Miller, H., DeLisa, J., Williams, K., Woodson, K., Jennette, K., Carrera, L., Villanueva, L., Norwick, M., Martinez, M., Rowley, M., Rutherford, M., Carrithers, M., Pliskin, N., Perez, N., Durkin, N., Maniar, N., Beety, R., Daspgupta, R., Ramchandran, R., Jaramillo, R., Hasek, S., Macias, S., Schuh, T., Ialacci, S., Bailey, C., Labbato, D., Hautmann, A., Smith, B., Nath, D., Meyer, J., DiFrancesco, K., Walkup, K., Pettinato, K., Curtis, L., Daher, J., Scott, S., Koberssy, Z., Mavar, C., Andrefsky, J., Merheb, A., Hernandez, C., Baissary, J., Atieh, O., Pereira, C., Carpenter, D., Raynor, J., Brunton, K., Podgoreanu, A., Bunch, P., Brown, R., O'Brien, S., Dickey, S., McNulty, S., Gajjar, V., Neale, A., Cohen, C., Escobar, C., Geary, E., Campanella, F., Anderson, K., Prestige, L., Guidotti-Breting, L., Biewer, M., Morton, M., Mathenia, N., Adeyemi, O., Hengst, S., Chi, W. N., Vanderloo, A., Caplan, A., Chen, J., Acree, M. E., Glickman, M., Nakhate, M., Dan, Z. N., Switzer, P., Aryal, S., Sanchez, J., Sims, L., Ferdinand, R., Mammadova, M., Grimes, C., Vidales, E., Pham, H. P., Lopez, J., Nielsen, L., Keller, M., Uruba, S., Hernandez, M., Patel, B., Lin, M., Umana-Sanchez, V., Pak, C., Gainer, J., Burr, R., Trapuzzano, A., Celso, B., Bienkowski, G., Bowman, J., Verdecia, J., Zerwekh, K., Serrano, L., Marotz, M., Propp, P., Sarig, Y., Murphy, A., Comfort, B., Brown, G., Torres, I., Klein, J., Reed, J., Walker, J., Moore, J., Tempest-Browning, L., Arain, M., Kemp, P., Sullivan, S., Obrien, S., Way, S., Chevalier, J., Sykes, C., Kruck, C., Kiriakopoulos, E., Sackett, L., Kaden, S., Bang, C., Hynes, M., Gallagher, T., Childers-Kakos, M., Zia, A., South, A., Oravets, A., Ferreyra, C., Glaze, C., Villanueva, D., Blystone, E., Pritchard, J., Alyward, L., Cooper, M., Chidester, M., Alderson, R., Clark, R., Hodder, S., Sarwari, A., Bardes, J., Juskowich, J., Welch, S., Civil, A., Bendl, A., Dicker, E., Hanson, H., Viola, H., Morinigo, J., Pantaleon, K., Marcon, K., Stone, K., Stewart, K., Evo-Ortega, L., Loizos, M., McVeety, M., Guliyeva, S., Watson, E., Pehel, S., Ko, T., Caropolo, L., Kocas, H. D., Fernandez, L., ODonnell, A., Saperia, C., Thai, D., Pathak, D., Keller, J., Olszewski, K., Clinton, K., Cherian, K., Dutton, L., Elepano, M., Lin, R., Mohapatra, S., Chen, T., Wroolie, T., Leang, Z., Shashidhar, S., Nguyen, T., Ravisankar, A., Weiden, B., Brown, D., Bolliger, D., Glesne, H., Dixon, J., Chebrolu, P., Gazali, Z., Hurst, W., Fry, A., Murthy, G., Grischo, G., Erickson, H., Gomez, I., Copeland, J., Galaz, J., Autry, L., Dilise-Russo, M., James, M., Kala, M., Marshell, N., Borwege, S., Vadovicky, S., Marsh, S., Hartley, W., Murtagh, L., Kennedy, A., Meltzer-Christensen, A., Stringham, C., Gaskin, E., Judd, M., Smith, R., Cote, S., Mahasenan, S., Bjorklund, T., Farner, C., Taylor, B., Soileau, B., Cote, C., Hromas, G., Scholler, I., Longoria, L., Heard, P., Johnson, H., Jones, J., Tragus, R., Harris, M., Pinones, A., Anderson, A., Hastings, G., Courtright, J., Hernandez, J., Jayakumar, M., Fischer, M., Sullivan, M., Solis, P., Harteloo, A., Elias-Warren, A., Nguyen, D., McDonald, D., Nguyen, H., Rau, H., Mernaugh, J., Logue, J., Pagulayan, K., Watanabe, K., Huden, K., Peabody, L., Mei, T., Ogunwuyi, C., Cobbina, E., Sankar, I., Nguyen, L., Fromm, N., Arnold, R., Ogu, S., Yuan, Y., Ibrahim, H., Szum, I., Patel, J., Sultan, S., Jazayeri, Y., Hatlen, T., Anderson, B., Munoz, I., Rhys, L., Wright, M., Vane, R., Kim, J., Diaz, L., Yee, N., Gruhn, R., Browngoetz, S., Decato, T., Johnson, E., Chand, A., Ortiz, E., Bottrill, K., Henderson, K., Hildebrand, L., Johnson, M., DeArmond, R., Hughes, T. 2025

    Abstract

    Importance: Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need.Objective: To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID.Design, Setting, and Participants: This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID.Interventions: Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks.Main Outcomes and Measures: Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days.Results: A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions.Conclusions and Relevance: This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID.Trial Registration: ClinicalTrials.gov Identifier: NCT05965739.

    View details for DOI 10.1001/jamaneurol.2025.4415

    View details for PubMedID 41212544

  • Longitudinal Patient-Reported Outcome Trajectories in Long COVID: Findings From the STOP-PASC Clinical Trial. Open forum infectious diseases Jagannathan, P., Hedlin, H., Liang, J. W., Shaw, B., Maestri, E., Lin, M., Utz, P. J., Singh, U., Geng, L. N., Bonilla, H. 2025; 12 (10): ofaf634

    Abstract

    Long COVID is a heterogeneous post-infectious condition. Although patient-reported outcome (PRO) measures for diagnosis or therapeutic monitoring have been adapted from related complex chronic illnesses, no PRO has been validated specifically in Long COVID. The STOP-PASC randomized, placebo-controlled trial of nirmatrelvir/ritonavir (NMV/r) in adults with Long COVID showed no overall treatment effect. This exploratory analysis aimed to identify distinct symptom trajectories and clinical characteristics associated with improvement or worsening over time.We performed latent class trajectory modeling (LCTM) on PRO measures-including the Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), PROMIS domains, and core symptoms-among 155 randomized participants. Participants were followed for 15 weeks with serial symptom assessments. Trajectory groups were identified using Bayesian Information Criteria and characterized using descriptive statistics and absolute standardized differences.LCTM revealed heterogeneity in symptom trajectories. Two groups emerged for PGIS (improving n = 17, persistent/severe n = 136) and PGIC (improving n = 130; worsening n = 22). PROMIS-Physical Function modeling identified four groups (improving, normal/mild, moderate, and severe), fatigue core symptom modeling identified three (improving; moderate; severe). Worsening groups had higher proportions of NMV/r-treated participants and greater prevalence of cardiovascular symptoms and low-dose naltrexone use. Improving groups had shorter time since infection and higher baseline physical function. No subgroup showed a clear benefit from NMV/r.Distinct PRO trajectories reflect the clinical heterogeneity of Long COVID. NMV/r showed no clear benefit across subgroups. These findings emphasize the need for validated, Long COVID-specific PRO instruments and targeted therapeutic trials tailored to Long COVID subtypes.

    View details for DOI 10.1093/ofid/ofaf634

    View details for PubMedID 41164784

    View details for PubMedCentralID PMC12560753

  • Wearable-derived Sleep Measurements are Associated with Long-COVID in the RECOVER Adult Cohort. Research square Parthasarathy, S., Brosnahan, S., Sieberts, S., Neto, E., Li, Y., Tummalacherla, M., Brown, H., Chow, S., Dunn, J., Haack, M., Islam, S. M., Jacobs-Diggs, M., Jiang, Y., Kossowsky, J., Prather, A., Raytselis, N., Salimi, N., Ayache, M., Bartram, L., Becker, J., Chung, A., DelAlcazar, J., Flaherman, V., Gibson, K., Go, M., Gouripeddi, R., Han, J., Hoffman, M., Jolley, S., Kelly, J., Koberssy, Z., Krishnan, J., Laiyemo, A., Lee-Iannotti, J., Levitan, E., Mazzotti, D., McComsey, G., Mehari, A., Okomura, M., Patterson, T., Peluso, M., Prasad, B., Quintero, O., Ryerson, A., Singh, P., Singh, U., Verduzco-Gutierrez, M., Whitesell, P., Williams, N., Wisnivesky, J., Mullington, J., Redline, S., Karlson, E. 2025

    Abstract

    Wearables yield a wide array of sleep-related measures that are relevant to Long COVID. We leveraged wearables-derived sleep measures (WDSM) to identify differences between individuals with Long COVID (LC) versus individuals with possible or no LC in the RECOVER adult cohort. We found significant associations between LC and reduced heart rate variability measured during sleep and increased nightly variability in sleep duration after adjusting for confounders. Moreover, LC was independently associated with lower sleep efficiency, greater variability of nighttime sleep timing, higher resting heart rate, lower respiratory rate during rapid eye movement (REM) sleep, prolonged REM sleep onset latency, worse global physical and mental health. Cluster analysis identified distinct multidimensional patterns of WDSM that are associated with LC and quality of life. Together, the strong association between WDSM, or WDSM clusters, with LC provides a potential biomarker for future validation efforts to detect LC and monitor treatment effectiveness.

    View details for DOI 10.21203/rs.3.rs-7422764/v1

    View details for PubMedID 40951275

  • Olfactory Dysfunction After SARS-CoV-2 Infection in the RECOVER Adult Cohort. JAMA network open Horwitz, L. I., Becker, J. H., Huang, W., Akintonwa, T., Hornig-Rohan, M. M., Maranga, G., Adams, D. R., Albers, M. W., Ayache, M., Berry, J., Brim, H., Bryan, T. W., Charney, A. W., Clark, R. A., Cortez, M. M., D'Anza, B., Davis, H., Donohue, S. E., Erdmann, N., Flaherman, V., Fong, T. G., Frontera, J. A., Goldberg, M. P., Goldman, J. D., Harkins, M. S., Hodder, S. L., Jacoby, V. L., Jagannathan, P., Jia, X., Kelly, J. D., Krishnan, J. A., Kumar, A., Laiyemo, A. O., Levitan, E. B., Martin, J. N., McCaffrey, K. M., McComsey, G. A., Metz, T. D., Murthy, G., Nguyen, H., Okumura, M., Parry, S., Parthasarathy, S., Patterson, T. F., Peluso, M. J., Sorochinsky, C., Walker, T., Wiegand, S. L., Wiley, Z., Wisnivesky, J., Ashktorab, H., Foulkes, A., Lee-Iannotti, J. K. 2025; 8 (9): e2533815

    Abstract

    Olfactory dysfunction is common after SARS-CoV-2 infection and has been associated with cognitive loss in other conditions. Formal testing is needed to characterize the presence, severity, and patterns of olfactory dysfunction.To characterize long-term olfactory dysfunction after SARS-CoV-2 infection.This prospective cohort study included adults enrolled in the Researching COVID to Enhance Recovery (RECOVER)-Adult study. All those with and a random sample of those without self-reported change or loss in smell or taste were offered olfactory testing, performed at 83 sites in 35 US states and territories. Participants included 2956 enrollees with prior infection (1393 with and 1563 without self-reported change or loss) and 569 without prior infection (9 with and 560 without self-reported change or loss in taste) who underwent olfactory testing a mean (SD) of 671.6 (417.8) days after the index date. Data were collected from October 29, 2021, to June 6, 2025.SARS-CoV-2 infection.Olfactory function, as defined by age- and sex-standardized performance on the University of Pennsylvania Smell Identification Test (UPSIT), a well-validated test comprising 40 unique odors.The study included 3525 participants with a mean (SD) age of 47.6 (15.2) years; of 3520 with data available, 2548 (72.4%) were female or intersex. Among 1393 infected participants with self-reported change or loss, 1111 (79.8%) had hyposmia on the UPSIT, including 321 (23.0%) with severe microsmia or anosmia. Among 1563 infected participants without self-reported change or loss, 1031 (66.0%) had hyposmia, including 128 (8.2%) with severe microsmia or anosmia. Participants with prior infection and self-reported change or loss scored at the 16th age- and sex-standardized UPSIT percentile, compared with the 23rd and 28th percentiles for those without self-reported change or loss with and without prior known infection, respectively. Younger women had scores corresponding to lower mean age- and sex-standardized percentiles. Among participants who self-reported change or loss in smell, those with abnormal UPSIT scores more often reported cognitive problems (742 of 1111 [66.8%]) than those with normal UPSIT scores (179 of 282 [63.5%]).In this cohort study of RECOVER-Adult participants, self-reported change or loss in smell or taste was an accurate signal of verified hyposmia, but a high rate of hyposmia among those with no reported change or loss was also observed. Formal smell testing may be considered in those with prior SARS-CoV-2 infection to diagnose occult hyposmia and counsel patients about risks.

    View details for DOI 10.1001/jamanetworkopen.2025.33815

    View details for PubMedID 40996759

  • Age-Related Changes in the Clinical Picture of Long COVID. Journal of the American Geriatrics Society Fain, M. J., Horne, B. D., Horwitz, L. I., Thaweethai, T., Greene, M., Hornig, M., Orkaby, A. R., Rosen, C., Ritchie, C. S., Ashktorab, H., Blachman, N., Brim, H., Emerson, S., Erdmann, N., Erlandson, K. M., de Erausquin, G., Fong, T., Geng, L. N., Gordon, H. S., Gully, J. R., Hadlock, J., Han, J., Huang, W., Jagannathan, P., Kelly, J. D., Klein, J. D., Krishnan, J. A., Levitan, E. B., McComsey, G. A., McDonald, D., Montgomery, A. P., O'Brien, L., Ofotokun, I., Patterson, T. F., Peluso, M. J., Pemu, P., Perlowski, A., Reiman, E. M., Sanon, M., Seshadri, S., Shellito, J., Sherif, Z. A., Shikuma, C., Singer, N. G., Singh, U., Trinity, J. D., Wisnivesky, J., Witvliet, M. G., Foulkes, A., Nikolich, J. Ž. 2025

    Abstract

    This study evaluated the impact of aging on the frequency and prevalent symptoms of Long COVID, also termed post-acute sequelae of SARS-CoV-2, using a previously developed Long COVID research index (LCRI) of 41 self-reported symptoms in which those with 12 or more points were classified as likely to have Long COVID.We analyzed community-dwelling participants ≥ 60 years old (2662 with prior infection, 461 controls) compared to participants 18-59 years (7549 infected, 728 controls) in the Researching COVID to Enhance Recovery adult (RECOVER-Adult) cohort ≥ 135 days post-onset.Compared to the Age 18-39 group, the adjusted odds of LCRI ≥ 12 were higher for the Age 40-49 group (odds ratio [OR] = 1.40, 95% confidence intervals [CI] = 1.21-1.61, p < 0.001) and 50-59 group (OR = 1.31, CI = 1.14-1.51, p < 0.001), similar for the Age 60-69 group (OR = 1.09, CI = 0.93-1.27, p = 0.299), and lower for the ≥ 70 group (OR = 0.68, CI = 0.54-0.85, p < 0.001). Participants ≥ 70 years had smaller adjusted differences between infected and uninfected symptom prevalence rates than those aged 18-39 for the following symptoms: hearing loss, fatigue, pain (including joint, back, chest pain and headache), post-exertional malaise, sleep disturbance, hair loss, palpitations, and sexual desire/capacity, making these symptoms less discriminating for Long COVID in older adults than in younger. Symptom clustering, as described in Thaweethai et al. (JAMA 2023) also exhibited age-related shifts: clusters 1 (anosmia and ageusia) and 2 (gastrointestinal, chronic cough and palpitations, without anosmia, ageusia or brain fog) were more likely, and clusters 3 (brain fog, but no loss of smell or taste) and 4 (a mix of symptoms) less likely to be found in older adults (relative risk ratios for clusters 3-4 ranging from 0.10-0.34, p < 0.001 vs. 18-39 year-olds).Within the limits of this observational study, we conclude that in community-dwelling older adults, aging alters the prevalence and pattern of reported Long COVID.

    View details for DOI 10.1111/jgs.70043

    View details for PubMedID 40888500

  • Single-Cell and Plasma Proteomics Do Not Differentiate Patients With and Without SARS-CoV-2 Antigenemia in Convalescence in a Cohort of 100 Patients. Open forum infectious diseases Pienkos, S., Swank, Z., Hamlin, R. E., Rao, M., Grant, P., Bonilla, H., Jacobson, K., Jagannathan, P., Singh, U., Walt, D. R., Subramanian, A., Blish, C. 2025; 12 (9): ofaf515

    Abstract

    Plasma samples obtained approximately 3 (n = 100) and 12 months (n = 78) after acute SARS-CoV-2 infection were tested for S1, spike, and N antigens. There were no significant differences in plasma proteins or single-cell protein expression levels on immune cells between those with and without plasma antigen detected.

    View details for DOI 10.1093/ofid/ofaf515

    View details for PubMedID 40926879

    View details for PubMedCentralID PMC12415173

  • Digital Biometric Measures in Long COVID: A Secondary Analysis of the STOP-PASC Randomized Clinical Trial. JAMA network open Gunturkun, F., Hedlin, H., Botzheim, B., Deng, Y., Bonilla, H., Jagannathan, P., Quach, T. C., Kim, S., Lin, M., O'Riordan, G., Tzeng, H., Adamowicz, L., Demanuele, C., Cai, X., Yang, P. C., Singh, U., Geng, L. N. 2025; 8 (8): e2526901

    Abstract

    Digital biometrics can be used to monitor disease, but there is limited research on their applications for assessing postacute sequelae of SARS-CoV-2 (PASC) or long COVID.To better understand digital biometric patterns in long COVID using wearable device technology and whether there are any differences between the nirmatrelvir-ritonavir and placebo-ritonavir intervention arms.This secondary analysis is an exploratory substudy of a placebo-controlled randomized clinical trial (Selective Trial of Paxlovid for PASC [STOP-PASC]) that was conducted from November 2022 to September 2023 at Stanford University. Trial participants were randomized, and a subset enrolled into the prespecified substudy.Participants were randomized 2:1 to receive oral nirmatrelvir (300 mg) and ritonavir (100 mg) or placebo-ritonavir twice daily for 15 days. Substudy participants were provided with a smartwatch and asked to wear it for 24 hours a day, 7 days a week for the 15-week study.Mean changes in digital biometric measures in physical activity, heart rate, and oxygen saturation tracked by a smartwatch. Biometric measures were summarized by treatment arm for each of 5 different time frames: baseline, treatment period, and 3 subsequent time intervals. Summary measure trajectories were clustered and demographics and clinical characteristics were compared among clusters using absolute standardized differences expressed in units of SDs.Of the 94 participants enrolled in the substudy, 50 (37 in nirmatrelvir-ritonavir and 13 in placebo-ritonavir) met the analysis eligibility criteria based on wear time and data completeness. These participants had a mean (SD) age of 42.7 (13.2) years and included 29 females (58.0%). Using mixed models for repeated measures, no significant differences were detected between the intervention arms in the change in biometric measures over time, consistent with the patient-reported outcomes in the STOP-PASC trial. In the overall substudy cohort, latent class mixed models and cluster analysis identified distinct longitudinal trajectories of long COVID over the 15-week study that tracked with different symptoms. Participants with lower daytime physical activity reported more severe fatigue (9 of 9 [100%] vs 21 of 23 [91.3%]; absolute standardized difference [ASD], 0.30), shortness of breath (9 of 9 [100%] vs 7 of 23 [30.4%]; ASD, 1.31), and cardiovascular symptoms (8 of 9 [88.9%] vs 12 of 23 [52.2%]; ASD, 0.70). Those with higher nighttime physical activity reported more gastrointestinal symptoms (2 of 3 [66.7%] vs 11 of 35 [31.4%]; ASD, 0.50). Additionally, participants with higher median daytime heart rates reported less fatigue (7 of 9 [77.8%] vs 39 of 40 [97.5%]; ASD, 0.63) and shortness of breath (3 of 9 [33.3%] vs 23 of 40 [57.5%]; ASD, 0.50) compared with those with lower heart rates.This secondary analysis identified distinct longitudinal trajectories of physiological and behavioral digital biometric measures captured from wearable devices that reflect the heterogeneity and track with different symptoms of long COVID. Digital biometric measures from wearable devices have promising utility for long COVID research.ClinicalTrials.gov Identifier: NCT05576662.

    View details for DOI 10.1001/jamanetworkopen.2025.26901

    View details for PubMedID 40810942

    View details for PubMedCentralID PMC12355292

  • Social Determinants of Health and Risk for Long COVID in the U.S. RECOVER-Adult Cohort. Annals of internal medicine Feldman, C. H., Santacroce, L., Bassett, I. V., Thaweethai, T., Alicic, R., Atchley-Challenner, R., Chung, A., Goldberg, M. P., Horowitz, C. R., Jacobson, K. B., Kelly, J. D., Knight, S., Lutrick, K., Mudumbi, P., Parthasarathy, S., Prendergast, H., Quintana, Y., Sharareh, N., Shellito, J., Sherif, Z. A., Taylor, B. D., Taylor, E., Tsevat, J., Wiley, Z., Williams, N. J., Yee, L., Aponte-Soto, L., Baissary, J., Berry, J., Charney, A. W., Costantine, M. M., Duven, A. M., Erdmann, N., Ernst, K. C., Feuerriegel, E. M., Flaherman, V. J., Go, M., Hawkins, K., Jacoby, V., John, J., Kelly, S., Kindred, E., Laiyemo, A., Levitan, E. B., Levy, B. D., Logue, J. K., Marathe, J. G., Martin, J. N., McComsey, G. A., Metz, T. D., Minor, T., Montgomery, A. P., Mullington, J. M., Ofotokun, I., Okumura, M. J., Peluso, M. J., Pogreba-Brown, K., Raissy, H., Rosas, J. M., Singh, U., VanWagoner, T., Clark, C. R., Karlson, E. W. 2025

    Abstract

    Social determinants of health (SDoH) contribute to disparities in SARS-CoV-2 infection, but their associations with long COVID are unknown.To determine associations between SDoH at the time of SARS-CoV-2 infection and risk for long COVID.Prospective observational cohort study.33 states plus Washington, DC, and Puerto Rico.Adults (aged ≥18 years) enrolled in RECOVER-Adult (Researching COVID to Enhance Recovery) between October 2021 and November 2023 who were within 30 days of SARS-CoV-2 infection; completed baseline SDoH, comorbidity, and pregnancy questionnaires; and were followed prospectively.Social risk factors from SDoH baseline questionnaires, ZIP code poverty and household crowding measures, and a weighted score of 11 or higher on the Long COVID Research Index 6 months after infection.Among 3787 participants, 418 (11%) developed long COVID. After adjustment for demographic characteristics, pregnancy, disability, comorbidities, SARS-CoV-2 severity, and vaccinations, financial hardship (adjusted marginal risk ratio [ARR], 2.36 [95% CI, 1.97 to 2.91]), food insecurity (ARR, 2.36 [CI, 1.83 to 2.98]), less than a college education (ARR, 1.60 [CI, 1.30 to 1.97]), experiences of medical discrimination (ARR, 2.37 [CI, 1.94 to 2.83]), skipped medical care due to cost (ARR, 2.87 [CI, 2.22 to 3.70]), and lack of social support (ARR, 1.79 [CI, 1.50 to 2.17]) were associated with increased risk for long COVID. Living in ZIP codes with the highest (vs. lowest) household crowding was also associated with greater risk (ARR, 1.36 [CI, 1.05 to 1.71]).Selection bias may influence observed associations and generalizability.Participants with social risk factors at the time of SARS-CoV-2 infection had greater risk for subsequent long COVID than those without. Future studies should determine whether social risk factor interventions mitigate long-term effects of SARS-CoV-2 infection.National Institutes of Health.

    View details for DOI 10.7326/ANNALS-24-01971

    View details for PubMedID 40720834

  • Metformin and Time to Sustained Recovery in Adults With COVID-19: The ACTIV-6 Randomized Clinical Trial. JAMA internal medicine Bramante, C. T., Stewart, T. G., Boulware, D. R., McCarthy, M. W., Gao, Y., Rothman, R. L., Mourad, A., Thicklin, F., Cohen, J. B., Garcia Del Sol, I. T., Ruiz-Unger, J., Shah, N. S., Mehta, M., Cardona, O. Q., Scott, J., Ginde, A. A., Castro, M., Jayaweera, D., Sulkowski, M., Gentile, N., McTigue, K., Felker, G. M., Collins, S., Dunsmore, S. E., Adam, S. J., Lindsell, C. J., Hernandez, A. F., Naggie, S., Accelerating COVID-19 Therapeutic Interventions and Vaccines-6 Study Group and Investigators, DeLong, A., Wilder, R., Hanna, G., Fraser, R., Ward, M., Weaver, S., McAdams, M. P., Korzekwinski, K., Oyelakin, M., Dockery, S., Adkins, R., Crow, M., Light, S., Morris, R., Nowell, E., Wells, K., Herbert, A., Stone, A., Heavlin, H., Brown, L., Brunson, S., Harding, T., Harrington, A., Beauchaine, M., Lindblom, K., Burns, A., Mourad, A., Hamm, M. E., Phillips, K. T., Vasey, A., Edwards, T., Nelson, D., Merritt, G., Nguyen, J., Denson, J., Arnold, J., Aamodt, D., Clark, D., Collins, J., Collins, S., Dixon, S., Gao, Y., Graves, J., Grindstaff, J., Harrell, F., Lai, J., Liao, V., Lopez, I., Manis, E., Mankowski, K., Marlin, J., Merkel, A., Nwosu, S., Obregon, S., Orozco, D., Prato, N., Rohde, M., Shirey-Rice, J., Vermillion, K., Smith, J., Tan, H., Vance, M., Weir, M., Bianchi, R., Premas, J., Gupta, M., Karawan, G., Lima, S., Ziomek, C., Arena, J., DeAlmeida, S., Malik, A., Bryce, J., Swint, S., Tiffany, B., Tanner, C., Sahelian, A., George-Adebayo, C., Adebayo, A., Ronan, T., Woods, A., Gallegos, C., Flys, T., Sloan, O., Olofintuyi, A., Samraj, J., Samraj, J., Averett, A., Slandzicki, A., Wallan, J., Vogel, C., Munoz, S., Kavtaradze, D., Watson, C., Singleton, D., Sevier, M., Rivon, M., Rao, S., Cantu, L., Krishna, A., Daugherty, H., Kerr, B., Evans, K., Spees, R., Marta, M., Amir, D., Collazo, J., Dolor, R., Vergara, L., Jordan, J., Burruss, V., Hurst, T., Rebolledo Esteinou, P. A., Ofotokun, I., Zhang, C., Traenkner, J., Atha, M. M., James, V., Rogers, M., Oragwu, C., Oguego, N., Pillai, R., Gabriel, A., Ghaly, E., Michal, M., Hassanien, G., Ismail, S., Samir, Y., Meltzer, A., Heidish, R. S., Loganathan, A., Brehaut, S., Roche, A., Koppinger, N., Baez, J., Pagan, I., Abdelsayed, D., Aziz, M., Robinson, P., Lozinski, G., Nguyen, J., Griffin, A., Morris, M., Love, N., Mattox, B., Martin, R., Pardue, V., Rowland, T., Reyes, L., Bacallao, N., Cienki, J., Yuan, Y., Li, J., Szeto, J., Stelmash, L., Mekhael, S., Morales Castillo, L., Gutierrez, A., Prieto, S., Amon, A., Barbera, A., Bugajski, A., Wills, W., Jacklin, K., Lamb, D., Harper, A., Stout, E., Griffin, M., Clark, N., Barsanti-Sekhar, M., Carbrera-Mendez, C., Evans, M. R., Maria, J., Raymond, O., Summers, J., Turner, T., Lenert, L., Panaccione, E., Miller, C., Wiley, H., Chan, A., Khizer, S., Adeyemi, O., Ning Chi, W., Chen, J., Morton-Jost, M., Castex, J., Quirch, A., Belani, H., Machicado, R., Bjornsson, B., Olivo, J., Maldonado, M., Vecchiarelli, A., Gaytan-Alvarez, D., Cherukuri, V., Alicic, R., Lambert, A. A., Urbat, C., Baxter, J., Cooper, A., Linn, D., Fisher, L., Patel, V., Patel, Y., Talati, R., Patel, P., Ellison, L., Roman, A., Harrison, J., Moy, J., Naquiallah, D., Shah, B., Jagannathan, P., Singh, U., O'Donnell, A., Jazayeri, Y., Gupta, A., Chandrasekar, N., Curtis, C., White, B., Dockery, M., Fortt, T., Fortt, A., Wilson, J., Marcelin, J., Farlow, B., Grady, C., Richwine, R., Pazier, P., Michelson, E., Watts, S., Kariyawasam, D., Rodriguez, L., Luis Garcia, J., Manresa, I., Achong, A. A., Garcia, M. C., Mahadevan, A., VandeWeerd, C., Lowenkron, J., Sappington, E., Roberts, M., Wang, J., Adams, M., Ding, X., Co, M., D'Andrea, M., Lim, S., Young, M., Wilson, M., Eastin, C., Cheathem, A., Nadeem, A., Walters, C., Powers-Fletcher, M., Brown, D., Miller, D., Mukunzi, S., Isache, C., Bowman, J., Martin, D., Duran, B., Schwasinger-Schmidt, T., Ast, A., Cornejo, A., Archer, A., Almanzar, M., Motel, V., Pullen, M., Bhat, N., Parra, D., Urbina, E., Arriaza, S., Sekikawa, A., Klawson, E., Weiland, N., Ostrosky-Zeichner, L., Patel, B., Umana, V., Nielsen, L., Grimes, C. Z., Patterson, T. F., Soileau, B. T., Jackson, P. E., Haughey, H. M., Vaidya-Tank, B., Gould, C., Goyal, P., Pangburn, H., Michalowski, L., Williamson, J., Wortham, B., Abbott, R., Umana, U., Alleyne, C., Witting, B., Armas, E., Perez Landaburo, R. O., De La Cruz, M., Ballmajo, M., Alvarez, J. 2025

    Abstract

    Importance: The effect of metformin on reducing symptom duration among outpatient adults with COVID-19 has not been studied.Objective: To assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2.Design, Setting, and Participants: The Accelerating COVID-19 Therapeutic Interventions and Vaccines platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, participants 30 years or older with confirmed SARS-CoV-2 infection and 2 or more COVID-19 symptoms for 7 days or less were included at 90 US sites.Interventions: Participants were randomized to receive metformin (titrated to 1500 mg, daily) or placebo for 14 days.Main Outcomes and Measures: The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving the study drug. Secondary outcomes included time to clinic visit, emergency department (ED) visit, hospitalization, or death. Safety events of interest were hypoglycemia and lactic acidosis.Results: Among 2991 participants who were randomized and received study drug, the median age was 47 (IQR, 38-58) years; 1895 (63.4%) were female, 25 (0.8%) were American Indian of Alaska Native, 77 (2.6%) were Asian, 350 (11.7%) were Black, African American, or African, 1392 (46.5%) identified as Hispanic or Latino, 8 (0.3%) were Native Hawaiian or other Pacific Islander, 2395 (80.1%) were White, and 2044 (68.3%) reported 2 or more doses of a SARS-CoV-2 vaccine. Among 1443 (48.2%) participants who received metformin and 1548 (51.8%) who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio, 0.96; 95% credible interval [CrI], 0.89-1.03; P for efficacy=.11). The median time to sustained recovery was 9 days (95% CI, 9-10) for metformin and 10 days (95% CI, 9-10) for placebo. No deaths were reported; 103 participants reported clinic visits, ED visits, or hospitalization: 54 in the metformin group and 49 in the placebo group (hazard ratio, 1.25; 95% CrI, 0.82-1.78; P for efficacy=.13). Overall, 35 (1.2%) reported ED visits or hospitalization (1.1% in the metformin and 1.3% in the placebo group). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. There were 4 episodes of participant-reported hypoglycemia in the placebo group and 2 in the metformin group.Conclusions and Relevance: In this randomized clinical trial, metformin was not shown to shorten the time to symptom resolution in low-risk adults with COVID-19. The median days to symptom resolution was numerically but not significantly lower for metformin. Safety was not a limitation in the study population.Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

    View details for DOI 10.1001/jamainternmed.2025.2570

    View details for PubMedID 40658388

  • Efficacy and safety of obeldesivir in low-risk, non-hospitalised patients with COVID-19 (OAKTREE): a phase 3, randomised, double-blind, placebo-controlled study. The Lancet. Infectious diseases Ogbuagu, O., Goldman, J. D., Gottlieb, R. L., Singh, U., Shinkai, M., Acloque, G., Fusco, D. N., Gonzalez, E., Kumar, P., Luetkemeyer, A., Lichtman, A., Mozaffarian, A., Koullias, Y., Hyland, R. H., Llewellyn, J., Osinusi, A., Duff, F., Humeniuk, R., Caro, L., Davies, S., Rodriguez, L., Hedskog, C., Chen, S., Etchevers, K., Nadig, P., Kohli, A., OAKTREE Trial Investigators, Abinante, M., Acloque, G., Acloque, J., Aguilera, A., Alvarez, G., Amaya, J., Aponte, M., Atwi, J., Azizad, M., Bacchelli, S., Barseghian, N., Bearie, B., Berenguer, R., Betancourt, G., Boghara, H., Carpio, J., Castillo Hernandez, L., Cedeno, J., Cheekati, V., Cook, P., Crofoot, G. E., Cubillas, M., Cueli, A., Cueto, A., Cueva, W., Daniel, D., Daniel, N., Diaz, J., Duardo-Guerra, Y., Duarte Martinez, R., Fakih, F., Felizarta, F., Fernandez, R., Fernandez Miro, H., Focil, A., Fusco, D., Galvez, O., Garcia, E., Garcia Ramirez, R., Garcia-Zuniga, A., Goisse, M., Gold, M., Gonzalez, A., Gonzalez, E., Gonzalez, J., Gonzalez, M., Gonzalez, P., Gonzalez, R., Gonzalez Vergara, F., Gonzalez-Rojas, Y., Gothard, S., Gottlieb, R., Haffizulla, J., Hernandez Loy, R., Hoover, K., Hussain, R., Igarashi, T., Iglesias, R., Issa, H., Jimenez, G., Jones, S., Kaplan, A., Kasarjian, J., Kohli, A., Kumar, P., Ledo-Sanchez, G., Luetkemeyer, A., Lupercio, R., Macias, F., Marsh, M., Martin, C., Mas, L., Mishkin, D., Mittal, S., Moises Gutierrez, J., Morado, A., Nozaki, M., Ono, R., Ortiz, F., Patel, R., Perez, R., Perez, G., Pfeffer, M., Pineiro Puebla, Y., Pruthi, J., Ramirez Navarro, A., Robaina, A., Rodriguez, R., Rosenthal, M., Sachdeva, Y., Saiger, S., Sanchez Cazau, D., Sato, Y., Shinkai, M., Sims, J., Somodevilla, G., Suarez, R., Tharmarajah, S., Torkan, B., Trevino, M., Upadhyay, H., Uribe, E., Vaca, C., Veras, L., Woolbert, L. 2025

    Abstract

    BACKGROUND: Obeldesivir is an oral nucleoside analogue prodrug antiviral that inhibits SARS-CoV-2 replication. We aimed to assess the efficacy, safety, and tolerability of obeldesivir for the treatment of COVID-19 in non-hospitalised individuals at low risk of progression to severe disease.METHODS: OAKTREE was a phase 3, randomised, double-blind, placebo-controlled trial in 107 centres (including research centres, primary care centres, and hospitals) in Japan and the USA. Low-risk, non-hospitalised adults and adolescents with mild-to-moderate COVID-19 were enrolled within 3 days of symptom onset. Eligible participants were randomly assigned 1:1 using permuted block randomisation (block size of four), stratified by historical completion of a primary COVID-19 vaccination series, to receive either oral obeldesivir 350 mg or matched placebo twice daily for 5 days. The primary efficacy endpoint was time to COVID-19 symptom alleviation by day 29, which was assessed in all randomly assigned participants who received one or more doses of study drug, had positive SARS-CoV-2 RT-PCR (per central laboratory testing) at baseline, and had COVID-19 symptom data (full analysis positive set). The primary safety endpoint was the incidence of adverse events and laboratory abnormalities and was assessed in all randomly assigned participants who received one or more doses of study drug. As a secondary endpoint we assessed change from baseline in nasal swab viral RNA copy number at day 5 in all randomly assigned participants who received one or more doses of study drug and had a quantifiable baseline value. This trial is registered with ClinicalTrials.gov, NCT05715528, and is complete.FINDINGS: Between Feb 13, 2023 and Oct 31, 2023, 1955 participants (1155 female and 800 male; 1698 White, 207 Black, 42 Asian, and eight Other) were randomly assigned and received at least one dose of either obeldesivir (n=979) or placebo (n=976). Overall, 1368 (70·0%) participants had completed a primary COVID-19 vaccination series and 1938 (99·6%) were seropositive for SARS-CoV-2 antibodies. There were 884 participants in each group in the full analysis positive set. Among those in the full analysis positive set who completed the symptom questionnaire (ie, who had COVID-19 symptom data; 879 obeldesivir, 882 placebo), median time to COVID-19 symptom alleviation was 5·9 days (95% CI 5·4-6·1) in the obeldesivir group and 6·0 days (5·8-6·3) in the placebo group (hazard ratio 1·099 [95% CI 0·997-1·211], p=0·068). The least-squares mean change from baseline in viral RNA copy number at day 5 was -2·13 log10 copies per mL (SE 0·04) and -1·95 log10 copies per mL (0·04) for the obeldesivir group (n=637) and placebo group (n=622), respectively, with a least-squares mean difference of -0·18 (95% CI -0·30 to -0·06) log10 copies per mL (p=0·0037). The safety profile was comparable between groups. 53 (5·4%) of 979 participants in the obeldesivir group and 56 (5·7%) of 976 participants in the placebo group had one or more treatment-emergent adverse events. 753 (77·5%) participants in the obeldesivir group and 757 (78·5%) participants in the placebo group had one or more graded laboratory abnormalities, most of which were grade 1 or 2.INTERPRETATION: Obeldesivir was generally safe and well tolerated, with greater reduction of SARS-CoV-2 viral RNA copy number versus placebo at day 5. However, obeldesivir did not significantly reduce time to symptom alleviation, possibly reflecting the challenges of assessing efficacy in this population in an era of high rates of vaccine-induced and natural immunity.FUNDING: Gilead Sciences.

    View details for DOI 10.1016/S1473-3099(25)00238-5

    View details for PubMedID 40675167

  • Exploring virulence and stress response in Entamoeba histolytica: insights from clinical strains. Microbiology spectrum Yanagawa, Y., Sharma, M., Izumiyama, S., Singh, U. 2025: e0050625

    Abstract

    Amebiasis, caused by the protozoan Entamoeba histolytica, is a significant parasitic infection affecting millions of people worldwide, particularly in developing regions. Elucidating the mechanisms by which this parasite invades host tissues and circumvents immune defenses is essential for advancing therapeutic strategies. Key virulence factors such as Gal/GalNAc lectin, amebapore, and proteases enable the parasite to adhere to, invade, and destroy host tissues. This study aimed to identify novel virulence-related genes in clinical E. histolytica strains by analyzing their gene expression profiles. We collected clinical isolates from asymptomatic individuals and patients with amoebic liver abscesses to perform RNA sequencing and compare their gene expression profiles. The analysis identified 14 differentially expressed genes between high-virulence and low-virulence strains. Among these, four candidate genes exhibited significant upregulation in the virulent strains. Functional assays demonstrated that the overexpression of these genes contributed to key virulence traits, including increased adhesion, complement resistance, and enhanced starch phagocytosis. Significantly, two of the four candidate genes, EHI_124550 and EHI_107170, which encode hypothetical proteins, exhibited a strong correlation with both oxidative stress response and complement resistance. These findings suggest that specific genes play crucial roles in the parasite's ability to evade the host immune system and establish infection in extraintestinal sites like the liver.IMPORTANCEThis study focuses on understanding how Entamoeba histolytica, the parasite responsible for amebiasis, affects over 50 million people globally. Our research is the first study to examine various clinical strains of the parasite, identifying key genes that influence its ability to attach to host cells (adhesion) and ingest them (phagocytosis), both critical processes for its ability to cause disease. Additionally, we discovered that these genes play a role in helping the parasite withstand environmental stress, such as oxidative stress and heat shock, which are part of the body's defense mechanisms. These findings are significant because they reveal potential targets for future treatments aimed at reducing the parasite's virulence, or disease-causing potential. Understanding how E. histolytica adapts and survives under hostile conditions will help in developing better strategies to combat amebiasis. These results provide new insights into a unique immune evasion strategy employed by a pathogen.

    View details for DOI 10.1128/spectrum.00506-25

    View details for PubMedID 40488464

  • Role of tRNA-Derived Fragments in Protozoan Parasite Biology. Cells Sharma, M., Singh, U. 2025; 14 (2)

    Abstract

    tRNA molecules are among the most fundamental and evolutionarily conserved RNA types, primarily facilitating the translation of genetic information from mRNA into proteins. Beyond their canonical role as adaptor molecules during protein synthesis, tRNAs have evolved to perform additional functions. One such non-canonical role for tRNAs is through the generation of tRNA-derived fragments via specific cleavage processes. These tRNA-derived small RNAs (tsRNAs) are present across all three domains of life, including in protozoan parasites. They are formed through the cleavage of the parent tRNA molecules at different sites, resulting in either tRNA halves or smaller fragments. The precise mechanisms underlying the synthesis of various tRNA-derived fragments, including the specific RNases involved, as well as their distinct functions and roles in parasite physiology, are not yet fully understood and remain an active area of ongoing research. However, their role in modulating gene expression, particularly during stress responses, is becoming increasingly evident. In this context, we discuss recent findings on the roles of tRNA-derived small RNA in various protozoan parasites. Furthermore, we investigate how these tsRNAs either modulate gene expression within the parasite itself or are packaged into extracellular vesicles to alter host gene expression, thereby promoting parasite survival and adaptation.

    View details for DOI 10.3390/cells14020115

    View details for PubMedID 39851543

  • Sex Differences in Long COVID. JAMA network open Shah, D. P., Thaweethai, T., Karlson, E. W., Bonilla, H., Horne, B. D., Mullington, J. M., Wisnivesky, J. P., Hornig, M., Shinnick, D. J., Klein, J. D., Erdmann, N. B., Brosnahan, S. B., Lee-Iannotti, J. K., Metz, T. D., Maughan, C., Ofotokun, I., Reeder, H. T., Stiles, L. E., Shaukat, A., Hess, R., Ashktorab, H., Bartram, L., Bassett, I. V., Becker, J. H., Brim, H., Charney, A. W., Chopra, T., Clifton, R. G., Deeks, S. G., Erlandson, K. M., Fierer, D. S., Flaherman, V. J., Fonseca, V., Gander, J. C., Hodder, S. L., Jacoby, V. L., Kotini-Shah, P., Krishnan, J. A., Kumar, A., Levy, B. D., Lieberman, D., Lin, J. J., Martin, J. N., McComsey, G. A., Moukabary, T., Okumura, M. J., Peluso, M. J., Rosen, C. J., Saade, G., Shah, P. K., Sherif, Z. A., Taylor, B. S., Tuttle, K. R., Urdaneta, A. E., Wallick, J. A., Wiley, Z., Zhang, D., Horwitz, L. I., Foulkes, A. S., Singer, N. G. 2025; 8 (1): e2455430

    Abstract

    A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)-Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.Self-reported sex (male, female) assigned at birth.Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

    View details for DOI 10.1001/jamanetworkopen.2024.55430

    View details for PubMedID 39841477

    View details for PubMedCentralID PMC11755195

  • 2024 Update of the RECOVER-Adult Long COVID Research Index. JAMA Geng, L. N., Erlandson, K. M., Hornig, M., Letts, R., Selvaggi, C., Ashktorab, H., Atieh, O., Bartram, L., Brim, H., Brosnahan, S. B., Brown, J., Castro, M., Charney, A., Chen, P., Deeks, S. G., Erdmann, N., Flaherman, V. J., Ghamloush, M. A., Goepfert, P., Goldman, J. D., Han, J. E., Hess, R., Hirshberg, E., Hoover, S. E., Katz, S. D., Kelly, J. D., Klein, J. D., Krishnan, J. A., Lee-Iannotti, J., Levitan, E. B., Marconi, V. C., Metz, T. D., Modes, M. E., Nikolich, J. Ž., Novak, R. M., Ofotokun, I., Okumura, M. J., Parthasarathy, S., Patterson, T. F., Peluso, M. J., Poppas, A., Quintero Cardona, O., Scott, J., Shellito, J., Sherif, Z. A., Singer, N. G., Taylor, B. S., Thaweethai, T., Verduzco-Gutierrez, M., Wisnivesky, J., McComsey, G. A., Horwitz, L. I., Foulkes, A. S. 2024

    Abstract

    Classification of persons with long COVID (LC) or post-COVID-19 condition must encompass the complexity and heterogeneity of the condition. Iterative refinement of the classification index for research is needed to incorporate newly available data as the field rapidly evolves.To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities.Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024.SARS-CoV-2 infection.Presence of LC and participant-reported symptoms.A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures.The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

    View details for DOI 10.1001/jama.2024.24184

    View details for PubMedID 39693079

  • Identification of two transcription factors that work coordinately to regulate early development inEntamoeba. mBio Lozano-Amado, D., Singh, U. 2024: e0225024

    Abstract

    The protozoan parasite Entamoeba has a life cycle that switches between infective cysts and invasive trophozoites. Encystation, a crucial process in parasite biology, is controlled by different mechanisms including transcriptional control. We identified two nuclear proteins in Entamoeba invadens, EIN_066100 and EIN_085620, that regulate parasite development by binding to a DNA motif (TCACTTTC) in the promoter regions of genes upregulated in the first 8 h of stage conversion. Overexpression of EIN_066100, a homolog of MAK16 protein, resulted in reduced amoebic proliferation without affecting encystation efficiency. Overexpression of EIN_085620, a protein with an RNA-recognition motif (RRM), led to increased encystation efficiency. Glutathione S-transferase (GST) pull down assays revealed that EIN_066100 interacts with EIN_085620 both in vivo and in vitro, and this interaction is mediated by the EIN_085620 RRM domain. By evaluating truncated proteins with deletions at either the N-terminal or C-terminal regions of EIN_066100, we elucidated the importance of its N-terminal region in proper protein localization, proliferation, encystation, and interaction with EIN_085620. Taken together, these results indicate a coordinated role of EIN_066100 and EIN_085620 in regulating Entamoeba development. This work sheds light on the molecular mechanisms in the earliest stages of Entamoeba encystation.IMPORTANCEAn important biological process in the biology of Entamoeba is stage conversion, which plays a crucial role in disease propagation, facilitating parasite survival outside the host and spreading to new hosts. Multiple mechanisms contribute to controlling the expression of amebic stage-specific genes such as epigenetic and transcriptional control. Identification of early transcriptional control regulators is crucial to understanding the initiation of the encystation cascade. We identified two nuclear proteins, EIN_066100 and EIN_085620, involved in the proliferation and developmental regulation of E. invadens. These proteins work by direct binding to each other and mediating encystation efficiency. Study of new regulators involved in Entamoeba development represents an important advance in a critical aspect of parasite biology.

    View details for DOI 10.1128/mbio.02250-24

    View details for PubMedID 39540742

  • Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution. Science translational medicine Hamlin, R. E., Pienkos, S. M., Chan, L., Stabile, M. A., Pinedo, K., Rao, M., Grant, P., Bonilla, H., Holubar, M., Singh, U., Jacobson, K. B., Jagannathan, P., Maldonado, Y., Holmes, S. P., Subramanian, A., Blish, C. A. 2024; 16 (773): eadr1032

    Abstract

    Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor-β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2-like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

    View details for DOI 10.1126/scitranslmed.adr1032

    View details for PubMedID 39536117

  • Engaging communities in therapeutics clinical research during pandemics: Experiences and lessons from the ACTIV COVID-19 therapeutics research initiative JOURNAL OF CLINICAL AND TRANSLATIONAL SCIENCE Wohl, D. A., Adam, S. J., Gibbs, K. W., Moskowitz, A. L., Ortel, T. L., Singh, U., Jilg, N., Evering, T. H., Fischer, W. A., Taiwo, B. O., Daar, E. S., Lindsell, C. J., Naggie, S., Rothman, R. L., Dunsmore, S. E., McAdams, M., Vail, J., Jayaweera, D. 2024; 8 (1)

    View details for DOI 10.1017/cts.2024.561

    View details for Web of Science ID 001331196100001

  • Engaging communities in therapeutics clinical research during pandemics: Experiences and lessons from the ACTIV COVID-19 therapeutics research initiative. Journal of clinical and translational science Wohl, D. A., Adam, S. J., Gibbs, K. W., Moskowitz, A. L., Ortel, T. L., Singh, U., Jilg, N., Evering, T. H., Fischer, W. A., Taiwo, B. O., Daar, E. S., Lindsell, C. J., Naggie, S., Rothman, R. L., Dunsmore, S. E., McAdams, M. P., Vail, J., Jayaweera, D. 2024; 8 (1): e156

    Abstract

    This manuscript addresses a critical topic: navigating complexities of conducting clinical trials during a pandemic. Central to this discussion is engaging communities to ensure diverse participation. The manuscript elucidates deliberate strategies employed to recruit minority communities with poor social drivers of health for participation in COVID-19 trials. The paper adopts a descriptive approach, eschewing analysis of data-driven efficacy of these efforts, and instead provides a comprehensive account of strategies utilized. The Accelerate COVID-19 Treatment Interventions and Vaccines (ACTIV) public-private partnership launched early in the COVID-19 pandemic to develop clinical trials to advance SARS-CoV-2 treatments. In this paper, ACTIV investigators share challenges in conducting research during an evolving pandemic and approaches selected to engage communities when traditional strategies were infeasible. Lessons from this experience include importance of community representatives' involvement early in study design and implementation and integration of well-developed public outreach and communication strategies with trial launch. Centralization and coordination of outreach will allow for efficient use of resources and the sharing of best practices. Insights gleaned from the ACTIV program, as outlined in this paper, shed light on effective strategies for involving communities in treatment trials amidst rapidly evolving public health emergencies. This underscores critical importance of community engagement initiatives well in advance of the pandemic.

    View details for DOI 10.1017/cts.2024.561

    View details for PubMedID 39540112

    View details for PubMedCentralID PMC11557280

  • Time to Sustained Recovery Among Outpatients With COVID-19 Receiving Montelukast vs Placebo: The ACTIV-6 Randomized Clinical Trial. JAMA network open Rothman, R. L., Stewart, T. G., Mourad, A., Boulware, D. R., McCarthy, M. W., Thicklin, F., Garcia Del Sol, I. T., Garcia, J. L., Bramante, C. T., Shah, N. S., Singh, U., Williamson, J. C., Rebolledo, P. A., Jagannathan, P., Schwasinger-Schmidt, T., Ginde, A. A., Castro, M., Jayaweera, D., Sulkowski, M., Gentile, N., McTigue, K., Felker, G. M., DeLong, A., Wilder, R., Collins, S., Dunsmore, S. E., Adam, S. J., Hanna, G. J., Shenkman, E., Hernandez, A. F., Naggie, S., Lindsell, C. J., Accelerating COVID-19 Therapeutic Interventions and Vaccines-6 Study Group and Investigators, Hanna, G., Fraser, R., Ward, M., Gamboa Jackson, J., McAdams, M. P., Vail, J., Korzekwinski, K., Oyelakin, M., Chopp, J., Randle, D., Dockery, S., Adkins, R., Crow, M., Nowell, E., Wells, K., Herbert, A., Stone, A., Heavlin, H., Brown, L., Harding, T., Harrington, A., Beauchaine, M., Lindblom, K., Burns, A., Aamodt, D., Collins, J., Dixon, S., Gao, Y., Graves, J., Grindstaff, J., Harrell, F., Lai, J., Liao, V., Lopez, I., Manis, E., Mankowski, K., Marlin, J., Merkel, A., Nwosu, S., Obregon, S., Orozco, D., Prato, N., Rhode, M., Shirey-Rice, J., Vermillion, K., Smith, J., Tan, H., Vance, M., Weir, M., Bianchi, R., Premas, J., Gupta, M., Karawan, G., Lima, S., Ziomek, C., Arena, J., DeAlmeida, S., Malik, A., Bryce, J., Swint, S., Ramin, S., Nataraj, J., Deider, J., Cruz, R., Ramirez, A. M., Henault, L., Marcus, J., Southwell, A., Jacques, G., Sexton, C., Tiffany, B., Tanner, C., Sahelian, A., George-Adebayo, C., Adebayo, A., Zapatero, J., Clement, J., Ronan, T., Woods, A., Gallegos, C., Flys, T., Sloan, O., Olofintuyi, A., Samraj, J., Vasbinder, A., Averett, A., Slandzicki, A., Wallen, J., Vogel, C., Munoz, S., Kavtaradze, D., Watson, C., Singleton, D., Sevier, M., Rivon, M., Del Pilar, A., Spangler, A., Rao, S., Cantu, L., Krishna, A., Daugherty, H., Kerr, B., Evans, K., Spees, R., Marta, M., Dolor, R., Vergara, L., Jordan, J., Burruss, V., Hurst, T., Ofotokun, I., Zhang, C., Traenkner, J., Atha, M. M., Prabhu, R., Klicka, K., Lightfeather, A., James, V., Rogers, M., Oragwu, C., Oguego, N., Pillai, R., Gabriel, A., Ghaly, E., Michal, M., Vasquez, M., Mamon, A., Sheets, M., Hassanien, G., Ismail, S., Samir, Y., Meltzer, A., Shahamatdar, S., Heidish, R. S., Loganathan, A., Brehaut, S., Roche, A., Mehta, M., Koppinger, N., Baez, J., Pagan, I., Abdelsayed, D., Aziz, M., Robinson, P., Lozinski, G., Nguyen, J., Griffin, A., Morris, M., Love, N., Mattox, B., Martin, R., Pardue, V., Rowland, T., Ruiz-Unger, J., Reyes, L., Zamora, Y., Bacallao, N., Cienki, J., Cohen, J., Yuan, Y., Li, J., Szeto, J., Stelmash, L., Mekhael, S., Morales Castillo, L., Gutierrez, A., Prieto, S., Amon, A., Barbera, A., Bugajski, A., Willis, W., Jacklin, K., Lamb, D., Harper, A., Stout, E., Griffin, M., Pyram-Bernard, N., Quintero, A., Clark, N., Barsanti-Sekhar, M., Carbrera-Mendez, C., Evans, M. R., Adhami, E., Carillo, G., Maria, J., Paudel, D., Raymond, O., Summers, J., Turner, T., Lenert, L., Panaccione, E., Szwast, E., Reynolds, A., Abdulghani, A., Vasoya, P., Miller, C., Wiley, H., Chan, A., Khizer, S., Adeyemi, O., Chi, W. N., Chen, J., Morton-Jost, M., Castex, J., Quirch, A., Belani, H., Machicado, R., Bjornsson, B., Olivo, J., Maldonado, M., Vecchiarelli, A., Gaytan-Alvarez, D., Cherukuri, V., Alicic, R., Lambert, A. A., Urbat, C., Baxter, J., Cooper, A., Linn, D., Fisher, L., Patel, V., Talati, R., Patel, P., Ellison, L., Roman, A., Harrison, J., Moy, J., Naquiallah, D., Shah, B., Quintero, O., Scott, J., Jazayeri, Y., O'Donnell, A., Pathak, D., Gupta, A., Chandrasekar, N., Curtis, C., White, B., Dockery, M., Fortt, T., Fortt, A., Jones-Ince, I., McKee, A., Wilson, J., Marcelin, J., Farlow, B., Grady, C., Richwine, R., Pazier, P., Michelson, E., Watts, S., Kariyawasam, D., Rodriguez, L., Manresa, I., Achong, A. A., Garcia, M. C., Khetpal, S., Posey, F., Mahadevan, A., Gnoni, M., Van de Weerd, C., Lowenkron, J., Sappington, E., Roberts, M., Wang, J., Adams, M., Ding, X., Co, M., D'Andrea, M., Lim, S., Swink, W., Bozant, E., Young, M., Wilson, M., Eastin, C., Cheathem, A., Nadeem, A., Walters, C., Powers-Fletcher, M., Brown, D., Miller, D., Mukunzi, S., Manning, B., Terry-White, M., Crizaldo, M. C., Isache, C., Bowman, J., Callaghan-Brown, A., Martin, D., Ast, A., Duran, B., Cornejo, A., Archer, A., Almanzar, M., Motel, V., Pullen, M., Anderson, B., Bhat, N., Parra, D., Campora, P., Robinson, M., Seithel, M., Kendrick, L., Helming, D., Pollock, K., Sekikawa, A., Klawson, E., Arnold, J., Weiland, N., Ostrosky-Zeichner, L., Patel, B., Umana, V., Nielsen, L., Grimes, C. Z., Patterson, T. F., Tragus, R., Soileau, B. T., Heath, T., Hinjosa, E., Gutierrez, C., Jackson, P. E., Hallowell, C., Haughey, H. M., Vaidya-Tank, B., Gould, C., Goyal, P., Sommers, S., Pangburn, H., Jones, C., Michalowski, L., Wortham, B., Abbott, R., Umana, U., Alleyne, C., Witting, B., Armas, E., Perez Landaburo, R. O., De La Cruz, M., Ballmajo, M., Alvarez, J. 2024; 7 (10): e2439332

    Abstract

    Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain.Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19.Design, Setting, and Participants: This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites.Interventions: Participants were randomized 1:1 to receive montelukast, 10 mg once daily, or matched placebo for 14 days.Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis.Results: Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P=.63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P=.48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group).Conclusions and Relevance: In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19.Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

    View details for DOI 10.1001/jamanetworkopen.2024.39332

    View details for PubMedID 39422912

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