197 results on '"Christine Johnston"'
Search Results
2. Immunogenicity of NVX-CoV2373 heterologous boost against SARS-CoV-2 variants
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Kirsten E. Lyke, Robert L. Atmar, Clara Dominguez Islas, Christine M. Posavad, Meagan E. Deming, Angela R. Branche, Christine Johnston, Hana M. El Sahly, Srilatha Edupuganti, Mark J. Mulligan, Lisa A. Jackson, Richard E. Rupp, Christina A. Rostad, Rhea N. Coler, Martín Bäcker, Angelica C. Kottkamp, Tara M. Babu, David Dobrzynski, Judith M. Martin, Rebecca C. Brady, Robert W. Frenck, Kumaravel Rajakumar, Karen Kotloff, Nadine Rouphael, Daniel Szydlo, Rahul PaulChoudhury, Janet I. Archer, Sonja Crandon, Brian Ingersoll, Amanda Eaton, Elizabeth R. Brown, M. Juliana McElrath, Kathleen M. Neuzil, David S. Stephens, Diane J. Post, Bob C. Lin, Leonid Serebryannyy, John H. Beigel, David C. Montefiori, Paul C. Roberts, and the DMID 21-0012 Study Group
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Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract As part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209.
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- 2023
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3. A linked physiologically based pharmacokinetic model for hydroxychloroquine and metabolite desethylhydroxychloroquine in SARS‐CoV‐2(−)/(+) populations
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Claire Steinbronn, Yashpal S. Chhonker, Jenell Stewart, Hannah Leingang, Kate B. Heller, Meighan L. Krows, Michael Paasche‐Orlow, Anna Bershteyn, Helen C. Stankiewicz Karita, Vaidehi Agrawal, Miriam Laufer, Raphael Landovitz, Mark Wener, Daryl J. Murry, Christine Johnston, Ruanne V. Barnabas, and Samuel L. M. Arnold
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)‐approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well‐established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID‐19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease‐related consequences of SARS‐CoV‐2 infection/COVID‐19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS‐CoV‐2 infection/COVID‐19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS‐CoV‐2(−)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS‐CoV‐2(−)/(+)participants, and incorporating COVID‐19‐associated changes in cytochrome P450 activity did not further improve model performance for the SARS‐CoV‐2(+) population.
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- 2023
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4. Hydroxychloroquine for treatment of non‐hospitalized adults with COVID‐19: A meta‐analysis of individual participant data of randomized trials
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Oriol Mitjà, Gilmar Reis, David R. Boulware, Adam M. Spivak, Ammar Sarwar, Christine Johnston, Brandon Webb, Michael D. Hill, Davey Smith, Peter Kremsner, Marla Curran, David Carter, Jim Alexander, Marc Corbacho, Todd C. Lee, Katherine Huppler Hullsiek, Emily G. McDonald, Rachel Hess, Michael Hughes, Jared M. Baeten, Ilan Schwartz, Luanne Metz, Lawrence Richer, Kara W. Chew, Eric Daar, David Wohl, and Michael Dunne
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID‐19). Conventional meta‐analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID‐19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID‐19. We evaluated the overall treatment group effect by log‐likelihood ratio test (−2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (−2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614–1.610; −2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta‐analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome‐coronavirus 2 viral clearance and COVID‐19 hospitalization did not show a clinical benefit of HCQ. Our meta‐analysis provides evidence to support the interruption in the use of HCQ in mild COVID‐19 outpatients to reduce progression to severe disease.
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- 2023
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5. Selective retention of virus-specific tissue-resident T cells in healed skin after recovery from herpes zoster
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Kerry J. Laing, Werner J. D. Ouwendijk, Victoria L. Campbell, Christopher L. McClurkan, Shahin Mortazavi, Michael Elder Waters, Maxwell P. Krist, Richard Tu, Nhi Nguyen, Krithi Basu, Congrong Miao, D. Scott Schmid, Christine Johnston, Georges M. G. M. Verjans, and David M. Koelle
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Science - Abstract
T cells are considered important for controlling skin infections. Here, the authors report that varicella-zoster virus-specific T cells preferentially persist as tissue-resident-memory T cells in rash-involved skin after recovery from zoster.
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- 2022
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6. Implementation of a fully remote randomized clinical trial with cardiac monitoring
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Jacob J. Mayfield, Neal A. Chatterjee, Peter A. Noseworthy, Jeanne E. Poole, Michael J. Ackerman, Jenell Stewart, Patricia J. Kissinger, John Dwyer, Sybil Hosek, Temitope Oyedele, Michael K. Paasche-Orlow, Kristopher Paolino, Paul A. Friedman, Chloe Waters, Jessica Moreno, Hannah Leingang, Kate B. Heller, Susan A. Morrison, Meighan L. Krows, Ruanne V. Barnabas, Jared Baeten, Christine Johnston, COVID-19 Early Treatment Team, and Arun R. Sridhar
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Medicine - Abstract
Mayfield et al. describe the implementation and feasibility of an exclusively remote randomized clinical trial of hydroxychloroquine and azithromycin for the treatment of COVID-19. The trial included monitoring of cardiovascular safety which was successfully done using digital technologies.
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- 2021
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7. Estimated economic burden of genital herpes and HIV attributable to herpes simplex virus type 2 infections in 90 low- and middle-income countries: A modeling study
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Sachin Silva, Houssein H. Ayoub, Christine Johnston, Rifat Atun, and Laith J. Abu-Raddad
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Medicine - Abstract
Background Economic losses due to herpes simplex infections in low- and middle-income countries (LMICs) are unknown. We estimated economic and quality-of-life losses due to genital herpes in 2019, in 90 LMICs, and from 2020 to 2030 in 45 countries in the World Health Organization (WHO) Africa. We additionally estimated economic losses due to human immunodeficiency virus (HIV) attributable to herpes simplex virus type 2 (HSV-2) infections. Methods and findings We estimated genital herpes-related spending on treatment, wage losses due to absenteeism, and reductions in quality of life, for individuals aged 15 to 49 years, living with genital herpes. Had HSV-2 had contributed to the transmission of HIV, we estimated the share of antiretroviral treatment costs and HIV-related wage losses in 2019 that can be attributed to incident and prevalent HSV-2 infections in 2018. For the former, we used estimates of HSV-2 incidence and prevalence from the global burden of disease (GBD) study. For the latter, we calculated population attributable fractions (PAFs), using the classic (Levin’s) epidemiological formula for polytomous exposures, with relative risks (RRs) reported in literature. To extend estimates from 2020 to 2030, we modeled the transmission of HSV-2 in 45 African countries using a deterministic compartmental mathematical model, structured by age, sex, and sexual activity, which was fitted to seroprevalence gathered from a systematic review and meta-regression analysis. In the 90 LMICs, genital herpes contributed to US$813.5 million in treatment and productivity losses in 2019 (range: US$674.4 to US$952.2 million). Given observed care-seeking and absenteeism, losses are in the range of US$29.0 billion (US$25.6 billion to US$34.5 billion). Quality-of-life losses in the amount of 61.7 million quality-adjusted life years (QALYs) are also possible (50.4 million to 74.2 million). The mean annual cost of treatment and wage losses per infection is US$183.00 (95% CI: US$153.60 to US$212.55); the mean annual cost of quality-of-life losses is US$343.27 (95% CI: 272.41 to 414.14). If HSV-2 has fueled the transmission of HIV, then seroprevalent HSV-2 cases in 2018 can account for 33.2% of the incident HIV infections in 2019, with an associated antiretroviral therapy (ART) cost of US$186.3 million (range: US$163.6 to US$209.5 million) and 28.6% of HIV-related wage losses (US$21.9 million; range: US$19.2 to US$27.4 million). In the WHO Africa region, the 3.9 million seroprevalent genital herpes cases from 2020 to 2030 contributed to US$700.2 million in treatment and productivity losses. Additionally, quality-of-life losses in the range of 88 million to 871 million QALYs are also possible. If HSV-2 has contributed to the transmission of HIV, then in 2020, the PAF of HIV due to prevalent HSV-2 will be 32.8% (95% CI: 26.7% to 29.9%) and due to incident infections will be 4.2% (95% CI: 2.6% to 3.4%). The PAF due to prevalent infections will decline to 31.0% by 2030 and incident infections to 3.6%. Though we have accounted for the uncertainty in the epidemiological and economic parameter values via the sensitivity analysis, our estimates still undervalue losses due to limiting to the 15- to 49-year-old population. Conclusions Economic losses due to genital herpes in LMICs can be large, especially when considering the lifelong nature of the disease. Quality-of-life losses outweigh spending on treatment and reductions in productivity. If HSV-2 has contributed to the spread of HIV in LMICs, then nearly one third of antiretroviral costs and HIV-related wage losses can be attributed to HSV-2. Given the magnitude of the combined losses, a vaccine against HSV-2 must be a global priority. In a modelling study, Dr Sachin Silva and colleagues estimate the economic burden of genital herpes and HIV attributable to herpes simplex virus type-2 infections in 90 low and middle income countries. Author summary Why was this study done? ▪ Economic losses due to herpes simplex virus type 2 (HSV-2) infections in low- and middle-income countries (LMICs) are unknown. ▪ Quality-of-life losses due to genital herpes in LMICs are also unknown, both in terms of their magnitude and their economic value. ▪ If HSV-2 has indeed fueled the spread of human immunodeficiency virus (HIV), as has been conjectured, then the share of HIV-related spending in LMICs that are attributable to HSV-2 infections are also unknown. What did the researchers do and find? ▪ We estimated direct and indirect economic losses and quality-of-life losses due to genital herpes in individuals between the aged of 15 to 49 living in 90 LMICs in 2019. ▪ We also estimated these costs in 45 countries in the World Health Organization (WHO) Africa region from 2020 to 2030, by constructing a mathematical model of HSV-2 dynamics to predict HSV-2 incidence and prevalence. ▪ We supplemented the 2019 estimates with the share of HIV-related spending in 2019 attributable HSV-2 infections in 2018. ▪ For the 90 LMICs, we found that treatment costs and productivity losses in 2019 are in the range of US$674.4 and US$952.2 million. ▪ Quality-of-life losses are in the range of 50.4 million to 74.2 million quality-adjusted life years (QALYs). ▪ Additionally, seroprevalent HSV-2 cases in 2019 can account for 33.2% of antiretroviral therapy (ART) costs for incident HIV cases and 28.6% of HIV-related wage. What do these findings mean? ▪ Economic losses due to genital herpes can be substantial, especially when considering the lifelong nature of the disease. ▪ The quality-of-life losses due to genital herpes outweigh spending on treatment and reduced productivity (on the order of US$212 billion). ▪ If HSV-2 has indeed contributed to the transmission of HIV, then nearly one third of antiretroviral costs and HIV-related wage losses add to these costs. ▪ Given the magnitude of the above losses in LMICs, a vaccine against HSV-2 should be a global priority.
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- 2022
8. Comparison of herpes simplex virus 1 genomic diversity between adult sexual transmission partners with genital infection.
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Molly M Rathbun, Mackenzie M Shipley, Christopher D Bowen, Stacy Selke, Anna Wald, Christine Johnston, and Moriah L Szpara
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Herpes simplex virus (HSV) causes chronic infection in the human host, characterized by self-limited episodes of mucosal shedding and lesional disease, with latent infection of neuronal ganglia. The epidemiology of genital herpes has undergone a significant transformation over the past two decades, with the emergence of HSV-1 as a leading cause of first-episode genital herpes in many countries. Though dsDNA viruses are not expected to mutate quickly, it is not yet known to what degree the HSV-1 viral population in a natural host adapts over time, or how often viral population variants are transmitted between hosts. This study provides a comparative genomics analysis for 33 temporally-sampled oral and genital HSV-1 genomes derived from five adult sexual transmission pairs. We found that transmission pairs harbored consensus-level viral genomes with near-complete conservation of nucleotide identity. Examination of within-host minor variants in the viral population revealed both shared and unique patterns of genetic diversity between partners, and between anatomical niches. Additionally, genetic drift was detected from spatiotemporally separated samples in as little as three days. These data expand our prior understanding of the complex interaction between HSV-1 genomics and population dynamics after transmission to new infected persons.
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- 2022
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9. HSV-2-Specific Human Female Reproductive Tract Tissue Resident Memory T Cells Recognize Diverse HSV Antigens
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David M. Koelle, Lichun Dong, Lichen Jing, Kerry J. Laing, Jia Zhu, Lei Jin, Stacy Selke, Anna Wald, Dana Varon, Meei-Li Huang, Christine Johnston, Lawrence Corey, and Christine M. Posavad
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HSV-2 ,CD8 ,CD4 ,epitope ,dendritic cell ,female reproductive tract immunology ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Antigen-specific TRM persist and protect against skin or female reproductive tract (FRT) HSV infection. As the pathogenesis of HSV differs between humans and model organisms, we focus on humans with well-characterized recurrent genital HSV-2 infection. Human CD8+ TRM persisting at sites of healed human HSV-2 lesions have an activated phenotype but it is unclear if TRM can be cultivated in vitro. We recovered HSV-specific TRM from genital skin and ectocervix biopsies, obtained after recovery from recurrent genital HSV-2, using ex vivo activation by viral antigen. Up to several percent of local T cells were HSV-reactive ex vivo. CD4 and CD8 T cell lines were up to 50% HSV-2-specific after sorting-based enrichment. CD8 TRM displayed HLA-restricted reactivity to specific HSV-2 peptides with high functional avidities. Reactivity to defined peptides persisted locally over several month and was quite subject-specific. CD4 TRM derived from biopsies, and from an extended set of cervical cytobrush specimens, also recognized diverse HSV-2 antigens and peptides. Overall we found that HSV-2-specific TRM are abundant in the FRT between episodes of recurrent genital herpes and maintain competency for expansion. Mucosal sites are accessible for clinical monitoring during immune interventions such as therapeutic vaccination.
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- 2022
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10. QT interval and arrhythmic safety of hydroxychloroquine monotherapy in coronavirus disease 2019
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Arun R. Sridhar, MBBS, MPH, Neal A. Chatterjee, MD, MSc, Basil Saour, MD, Dan Nguyen, MD, Elizabeth A. Starnes, ARNP, Christine Johnston, MD, MPH, Margaret L. Green, MD, MPH, Gregory A. Roth, MD, and Jeanne E. Poole, MD, FHRS
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Coronavirus ,Electrocardiogram ,Hydroxychloroquine ,QT interval ,Ventricular arrhythmia ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Observational studies have suggested increased arrhythmic and cardiovascular risk with the combination use of hydroxychloroquine (HCQ) and azithromycin in patients with coronavirus disease 2019 (COVID-19). Objective: The arrhythmic safety profile of HCQ monotherapy, which remains under investigation as a therapeutic and prophylactic agent in COVID-19, is less established and we sought to evaluate this. Methods: In 245 consecutive patients with COVID-19 admitted to the University of Washington hospital system between March 9, 2020, and May 10, 2020, we identified 111 treated with HCQ monotherapy. Patients treated with HCQ underwent a systematic arrhythmia and QT interval surveillance protocol including serial electrocardiograms (ECG) (baseline, following second HCQ dose). The primary endpoint was in-hospital sustained ventricular arrhythmia or arrhythmic cardiac arrest. Secondary endpoints included clinically significant QTc prolongation. Results: A total of 111 patients with COVID-19 underwent treatment with HCQ monotherapy (mean age 62 ± 16 years, 44 women [39%], serum creatinine 0.9 [interquartile range 0.4] mg/dL). There were no instances of sustained ventricular arrythmia or arrhythmic cardiac arrest. In 75 patients with serial ECGs, clinically significant corrected QT (QTc) prolongation was observed in a minority (n = 5 [7%]). In patients with serial ECGs, there was no significant change in the QTc interval in prespecified subgroups of interest, including those with prevalent cardiovascular disease or baseline use of renin-angiotensin-aldosterone axis inhibitors. Conclusions: In the context of a systematic monitoring protocol, HCQ monotherapy in hospitalized COVID-19 patients was not associated with malignant ventricular arrhythmia. A minority of patients demonstrated clinically significant QTc prolongation during HCQ therapy.
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- 2020
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11. Tissue-Resident-Memory CD8+ T Cells Bridge Innate Immune Responses in Neighboring Epithelial Cells to Control Human Genital Herpes
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Tao Peng, Khamsone Phasouk, Catherine N. Sodroski, Sijie Sun, Yon Hwangbo, Erik D. Layton, Lei Jin, Alexis Klock, Kurt Diem, Amalia S. Magaret, Lichen Jing, Kerry Laing, Alvason Li, Meei-Li Huang, Max Mertens, Christine Johnston, Keith R. Jerome, David M. Koelle, Anna Wald, David M. Knipe, Lawrence Corey, and Jia Zhu
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tissue-resident-memory T cells (TRM) ,innate antiviral response ,cell-intrinsic immunity ,IFI16 restriction factor ,tissue microenvironment ,human genital herpes ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Tissue-resident-memory T cells (TRM) populate the body’s barrier surfaces, functioning as frontline responders against reencountered pathogens. Understanding of the mechanisms by which CD8TRM achieve effective immune protection remains incomplete in a naturally recurring human disease. Using laser capture microdissection and transcriptional profiling, we investigate the impact of CD8TRM on the tissue microenvironment in skin biopsies sequentially obtained from a clinical cohort of diverse disease expression during herpes simplex virus 2 (HSV-2) reactivation. Epithelial cells neighboring CD8TRM display elevated and widespread innate and cell-intrinsic antiviral signature expression, largely related to IFNG expression. Detailed evaluation via T-cell receptor reconstruction confirms that CD8TRM recognize viral-infected cells at the specific HSV-2 peptide/HLA level. The hierarchical pattern of core IFN-γ signature expression is well-conserved in normal human skin across various anatomic sites, while elevation of IFI16, TRIM 22, IFITM2, IFITM3, MX1, MX2, STAT1, IRF7, ISG15, IFI44, CXCL10 and CCL5 expression is associated with HSV-2-affected asymptomatic tissue. In primary human cells, IFN-γ pretreatment reduces gene transcription at the immediate-early stage of virus lifecycle, enhances IFI16 restriction of wild-type HSV-2 replication and renders favorable kinetics for host protection. Thus, the adaptive immune response through antigen-specific recognition instructs innate and cell-intrinsic antiviral machinery to control herpes reactivation, a reversal of the canonical thinking of innate activating adaptive immunity in primary infection. Communication from CD8TRM to surrounding epithelial cells to activate broad innate resistance might be critical in restraining various viral diseases.
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- 2021
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12. Distinct populations of antigen-specific tissue-resident CD8+ T cells in human cervix mucosa
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Tao Peng, Khamsone Phasouk, Emily Bossard, Alexis Klock, Lei Jin, Kerry J. Laing, Christine Johnston, Noel A. Williams, Julie L. Czartoski, Dana Varon, Annalyssa N. Long, Jason H. Bielas, Thomas M. Snyder, Harlan Robins, David M. Koelle, M. Juliana McElrath, Anna Wald, Lawrence Corey, and Jia Zhu
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Immunology ,Virology ,Medicine - Abstract
The ectocervix is part of the lower female reproductive tract (FRT), which is susceptible to sexually transmitted infections (STIs). Comprehensive knowledge of the phenotypes and T cell receptor (TCR) repertoire of tissue-resident memory T cells (TRMs) in the human FRT is lacking. We took single-cell RNA-Seq approaches to simultaneously define gene expression and TCR clonotypes of the human ectocervix. There were significantly more CD8+ than CD4+ T cells. Unsupervised clustering and trajectory analysis identified distinct populations of CD8+ T cells with IFNGhiGZMBloCD69hiCD103lo or IFNGloGZMBhiCD69medCD103hi phenotypes. Little overlap was seen between their TCR repertoires. Immunofluorescence staining showed that CD103+CD8+ TRMs were preferentially localized in the epithelium, whereas CD69+CD8+ TRMs were distributed evenly in the epithelium and stroma. Ex vivo assays indicated that up to 14% of cervical CD8+ TRM clonotypes were HSV-2 reactive in HSV-2–seropositive persons, reflecting physiologically relevant localization. Our studies identified subgroups of CD8+ TRMs in the human ectocervix that exhibited distinct expression of antiviral defense and tissue residency markers, anatomic locations, and TCR repertoires that target anatomically relevant viral antigens. Optimization of the location, number, and function of FRT TRMs is an important approach for improving host defenses to STIs.
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- 2021
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13. Examining the dynamics of Epstein-Barr virus shedding in the tonsils and the impact of HIV-1 coinfection on daily saliva viral loads.
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Catherine M Byrne, Christine Johnston, Jackson Orem, Fred Okuku, Meei-Li Huang, Habibur Rahman, Anna Wald, Lawrence Corey, Joshua T Schiffer, Corey Casper, Daniel Coombs, and Soren Gantt
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Biology (General) ,QH301-705.5 - Abstract
Epstein-Barr virus (EBV) is transmitted by saliva and is a major cause of cancer, particularly in people living with HIV/AIDS. Here, we describe the frequency and quantity of EBV detection in the saliva of Ugandan adults with and without HIV-1 infection and use these data to develop a novel mathematical model of EBV infection in the tonsils. Eligible cohort participants were not taking antiviral medications, and those with HIV-1 infection had a CD4 count >200 cells/mm3. Over a 4-week period, participants provided daily oral swabs that we analysed for the presence and quantity of EBV. Compared with HIV-1 uninfected participants, HIV-1 coinfected participants had an increased risk of EBV detection in their saliva (IRR = 1.27, 95% CI = 1.10-1.47) and higher viral loads in positive samples. We used these data to develop a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and immune response within the tonsillar epithelium to analyse potential factors that may cause EBV infection to be more severe in HIV-1 coinfected participants. The model, fit using Approximate Bayesian Computation, showed high fidelity to daily oral shedding data and matched key summary statistics. When evaluating how model parameters differed among participants with and without HIV-1 coinfection, results suggest HIV-1 coinfected individuals have higher rates of B cell reactivation, which can seed new infection in the tonsils and lower rates of an EBV-specific immune response. Subsequently, both these traits may explain higher and more frequent EBV detection in the saliva of HIV-1 coinfected individuals.
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- 2021
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14. Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial
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Christine Johnston, Elizabeth R. Brown, Jenell Stewart, Helen C.Stankiewicz Karita, Patricia J. Kissinger, John Dwyer, Sybil Hosek, Temitope Oyedele, Michael K. Paasche-Orlow, Kristopher Paolino, Kate B. Heller, Hannah Leingang, Harald S. Haugen, Tracy Q. Dong, Anna Bershteyn, Arun R. Sridhar, Jeanne Poole, Peter A. Noseworthy, Michael J. Ackerman, Susan Morrison, Alexander L. Greninger, Meei-Li Huang, Keith R. Jerome, Mark H. Wener, Anna Wald, Joshua T. Schiffer, Connie Celum, Helen Y. Chu, Ruanne V. Barnabas, and Jared M. Baeten
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Coronavirus ,COVID-19 ,SARS-CoV-2 ,Hydroxychloroquine ,Azithromycin ,Early treatment ,Medicine (General) ,R5-920 - Abstract
Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4–6) in HCQ, 6 days (95% CI=4–8) in HCQ/AZ, and 8 days (95% CI=6–10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01–2.60, p = 0.047) but not HCQ/AZ (HR=1.25, p = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63–1.64, p = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57–1.45, p = 0.70). Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.Trial registration ClinicalTrials.gov number NCT04354428
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- 2021
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15. The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study
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Nicky J Welton, Peter Vickerman, Katherine M E Turner, Christine Johnston, Katharine Jane Looker, Charlotte James, Marie-Claude Boily, and Sami L Gottlieb
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Medicine (General) ,R5-920 ,Infectious and parasitic diseases ,RC109-216 - Abstract
IntroductionHerpes simplex virus (HSV) infection can cause painful, recurrent genital ulcer disease (GUD), which can have a substantial impact on sexual and reproductive health. HSV-related GUD is most often due to HSV type 2 (HSV-2), but may also be due to genital HSV type 1 (HSV-1), which has less frequent recurrent episodes than HSV-2. The global burden of GUD has never been quantified. Here we present the first global and regional estimates of GUD due to HSV-1 and HSV-2 among women and men aged 15–49 years old.MethodsWe developed a natural history model reflecting the clinical course of GUD following HSV-2 and genital HSV-1 infection, informed by a literature search for data on model parameters. We considered both diagnosed and undiagnosed symptomatic infection. This model was then applied to existing infection estimates and population sizes for 2016. A sensitivity analysis was carried out varying the assumptions made.ResultsWe estimated that 187 million people aged 15–49 years had at least one episode of HSV-related GUD globally in 2016: 5.0% of the world’s population. Of these, 178 million (95% of those with HSV-related GUD) had HSV-2 compared with 9 million (5%) with HSV-1. GUD burden was highest in Africa, and approximately double in women compared with men. Altogether there were an estimated 8 billion person-days spent with HSV-related GUD globally in 2016, with 99% of days due to HSV-2. Taking into account parameter uncertainty, the percentage with at least one episode of HSV-related GUD ranged from 3.2% to 7.9% (120–296 million). However, the estimates were sensitive to the model assumptions.ConclusionOur study represents a first attempt to quantify the global burden of HSV-related GUD, which is large. New interventions such as HSV vaccines, antivirals or microbicides have the potential to improve the quality of life of millions of people worldwide.
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- 2020
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16. Parent Involvement in Positive Behaviour Intervention and Supports in Australia: Teacher and Parent/Caregiver Perspectives
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Michelle Rose, Mary Mooney, Christine Johnston, and Roberto H. Parada
- Abstract
Positive Behaviour Intervention and Supports (PBIS) is a framework for defining, teaching, and supporting appropriate social and academic behaviour in the school setting. This framework is widely implemented across the world, including Australia. Studies evaluating the effectiveness of PBIS confirm a relationship between implementation fidelity and student outcomes. Abundant literature highlights the significance of parent involvement (PI) on children's social and academic outcomes. However, a consistently and surprisingly under researched component of PBIS is the involvement and influence of parents/caregivers. This article presents the findings of an original qualitative study using stakeholder interviews and artefact analysis to assess parent/caregiver involvement during PBIS implementation in two primary schools in South-West Sydney, Australia. These findings indicate that parent/caregiver involvement in PBIS implementation was interpreted differently by teachers and parents/caregivers and that there is potential for the development of improved methods to engage parents/caregivers more effectively in schools. Reframing parent/caregiver involvement in PBIS to address cultural sensitivities can progressively influence and stabilise this involvement to positively affect the sustainability, effectiveness and fidelity of PBIS. Limitations of the study together with recommendations for future practice are discussed.
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- 2024
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- View/download PDF
17. Ultrasensitive Capture of Human Herpes Simplex Virus Genomes Directly from Clinical Samples Reveals Extraordinarily Limited Evolution in Cell Culture
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Alexander L. Greninger, Pavitra Roychoudhury, Hong Xie, Amanda Casto, Anne Cent, Gregory Pepper, David M. Koelle, Meei-Li Huang, Anna Wald, Christine Johnston, and Keith R. Jerome
- Subjects
HSV-1 ,HSV-2 ,capture sequencing ,culture ,dual-strain infection ,genomics ,Microbiology ,QR1-502 - Abstract
ABSTRACT Herpes simplex viruses (HSVs) are difficult to sequence due to their large DNA genome, high GC content, and the presence of repeats. To date, most HSV genomes have been recovered from culture isolates, raising concern that these genomes may not accurately represent circulating clinical strains. We report the development and validation of a DNA oligonucleotide hybridization panel to recover nearly complete HSV genomes at abundances up to 50,000-fold lower than previously reported. Using copy number information on herpesvirus and host DNA background via quantitative PCR, we developed a protocol for pooling for cost-effective recovery of more than 50 HSV-1 or HSV-2 genomes per MiSeq run. We demonstrate the ability to recover >99% of the HSV genome at >100× coverage in 72 h at viral loads that allow whole-genome recovery from latently infected ganglia. We also report a new computational pipeline for rapid HSV genome assembly and annotation. Using the above tools and a series of 17 HSV-1-positive clinical swabs sent to our laboratory for viral isolation, we show limited evolution of HSV-1 during viral isolation in human fibroblast cells compared to the original clinical samples. Our data indicate that previous studies using low-passage-number clinical isolates of herpes simplex viruses are reflective of the viral sequences present in the lesion and thus can be used in phylogenetic analyses. We also detect superinfection within a single sample with unrelated HSV-1 strains recovered from separate oral lesions in an immunosuppressed patient during a 2.5-week period, illustrating the power of direct-from-specimen sequencing of HSV. IMPORTANCE Herpes simplex viruses affect more than 4 billion people across the globe, constituting a large burden of disease. Understanding the global diversity of herpes simplex viruses is important for diagnostics and therapeutics as well as cure research and tracking transmission among humans. To date, most HSV genomics has been performed on culture isolates and DNA swabs with high quantities of virus. We describe the development of wet-lab and computational tools that enable the accurate sequencing of near-complete genomes of HSV-1 and HSV-2 directly from clinical specimens at abundances >50,000-fold lower than previously sequenced and at significantly reduced cost. We use these tools to profile circulating HSV-1 strains in the community and illustrate limited changes to the viral genome during the viral isolation process. These techniques enable cost-effective, rapid sequencing of HSV-1 and HSV-2 genomes that will help enable improved detection, surveillance, and control of this human pathogen.
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- 2018
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18. Dual-strain genital herpes simplex virus type 2 (HSV-2) infection in the US, Peru, and 8 countries in sub-Saharan Africa: A nested cross-sectional viral genotyping study.
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Christine Johnston, Amalia Magaret, Pavitra Roychoudhury, Alexander L Greninger, Daniel Reeves, Joshua Schiffer, Keith R Jerome, Cassandra Sather, Kurt Diem, Jairam R Lingappa, Connie Celum, David M Koelle, and Anna Wald
- Subjects
Medicine - Abstract
BackgroundQuantitative estimation of the extent to which the immune system's protective effect against one herpes simplex virus type 2 (HSV-2) infection protects against infection with additional HSV-2 strains is important for understanding the potential for HSV-2 vaccine development. Using viral genotyping, we estimated the prevalence of HSV-2 dual-strain infection and identified risk factors.Methods and findingsPeople with and without HIV infection participating in HSV-2 natural history studies (University of Washington Virology Research Clinic) and HIV prevention trials (HIV Prevention Trials Network 039 and Partners in Prevention HSV/HIV Transmission Study) in the US, Africa, and Peru with 2 genital specimens each containing ≥105 copies herpes simplex virus DNA/ml collected a median of 5 months apart (IQR: 2-11 months) were included. It is unlikely that 2 strains would be detected in the same sample simultaneously; therefore, 2 samples were required to detect dual-strain infection. We identified 85 HSV-2 SNPs that, in aggregate, could determine whether paired HSV-2 strains were the same or different with >90% probability. These SNPs were then used to create a customized high-throughput array-based genotyping assay. Participants were considered to be infected with more than 1 strain of HSV-2 if their samples differed by ≥5 SNPs between the paired samples, and dual-strain infection was confirmed using high-throughput sequencing (HTS). We genotyped pairs of genital specimens from 459 people; 213 (46%) were men, the median age was 34 years (IQR: 27-44), and 130 (28%) were HIV seropositive. Overall, 272 (59%) people were from the US, 59 (13%) were from Peru, and 128 (28%) were from 8 countries in Africa. Of the 459 people, 18 (3.9%) met the criteria for dual-strain infection. HTS and phylogenetic analysis of paired specimens confirmed shedding of 2 distinct HSV-2 strains collected at different times in 17 pairs, giving an estimated dual-strain infection prevalence of 3.7% (95% CI = 2.0%-5.4%). Paired samples with dual-strain infection differed by a median of 274 SNPs in the UL_US region (range 129-413). Matching our observed dual-strain infection frequency to simulated data of varying prevalences and allowing only 2 samples per person, we inferred the true prevalence of dual-strain infection to be 7%. In multivariable analysis, controlling for HIV status and continent of origin, people from Africa had a higher risk for dual-strain infection (risk ratio [RR] = 9.20, 95% CI = 2.05-41.32), as did people who were HIV seropositive (RR = 4.06, 95% CI = 1.42-11.56).ConclusionsHSV-2 dual-strain infection was detected in 3.7% of paired samples from individual participants, and was more frequent among people with HIV infection. Simulations suggest that the true prevalence of dual-strain infection is 7%. Our data indicate that naturally occurring immunity to HSV-2 may be protective against infection with a second strain. This study is limited by the inability to determine the timing of acquisition of the second strain.
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- 2017
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19. Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract
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Joshua T Schiffer, David Swan, Ramzi Al Sallaq, Amalia Magaret, Christine Johnston, Karen E Mark, Stacy Selke, Negusse Ocbamichael, Steve Kuntz, Jia Zhu, Barry Robinson, Meei-Li Huang, Keith R Jerome, Anna Wald, and Lawrence Corey
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Herpes simplex ,Mucosal immunity ,Mathematical modeling ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in
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- 2013
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20. Impact of HIV infection and Kaposi sarcoma on human herpesvirus-8 mucosal replication and dissemination in Uganda.
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Christine Johnston, Jackson Orem, Fred Okuku, Mary Kalinaki, Misty Saracino, Edward Katongole-Mbidde, Merle Sande, Allan Ronald, Keith McAdam, Meei-Li Huang, Linda Drolette, Stacy Selke, Anna Wald, Lawrence Corey, and Corey Casper
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Medicine ,Science - Abstract
Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS.Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR).78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p
- Published
- 2009
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21. Genital Herpes Infection
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Nicholas Van Wagoner, Fuad Qushair, and Christine Johnston
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Microbiology (medical) ,Infectious Diseases - Published
- 2023
22. Using time‐weighted average change from baseline of SARS‐CoV‐2 viral load to assess impact of hydroxychloroquine as postexposure prophylaxis and early treatment for COVID‐19
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Raaka Kumbhakar, Moni Neradilek, Ruanne V. Barnabas, Jenell Stewart, Helen C. Stankiewicz Karita, Raphael J. Landovitz, Patricia J. Kissinger, Keith R. Jerome, Michael K. Paasche‐Orlow, Anna Bershteyn, Helen Y. Chu, Kathleen M. Neuzil, Alexander L. Greninger, Alfred Luk, Anna Wald, Elizabeth R. Brown, and Christine Johnston
- Subjects
Infectious Diseases ,SARS-CoV-2 ,Virology ,COVID-19 ,Humans ,Viral Load ,Hydroxychloroquine ,COVID-19 Drug Treatment - Abstract
Two randomized controlled trials demonstrated no clinical benefit of hydroxychloroquine (HCQ) for either postexposure prophylaxis or early treatment of SARS-CoV-2 infection. Using data from these studies, we calculated the time-weighted average change from baseline SARS-CoV-2 viral load and demonstrated that HCQ did not affect viral clearance.
- Published
- 2022
23. Diagnosis and Management of Genital Herpes: Key Questions and Review of the Evidence for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines
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Christine, Johnston
- Subjects
Counseling ,Male ,Microbiology (medical) ,Herpes Genitalis ,Infectious Diseases ,Herpesvirus 2, Human ,Sexually Transmitted Diseases ,Humans ,Female ,Herpesvirus 1, Human ,Centers for Disease Control and Prevention, U.S ,United States - Abstract
Genital herpes, caused by herpes simplex virus (HSV) type 1 or type 2, is a prevalent sexually transmitted infection (STI). Given that HSV is an incurable infection, there are important concerns about appropriate use of diagnostic tools, management of infection, prevention of transmission to sexual partners, and appropriate counseling. In preparation for updating the Centers for Disease Control and Prevention (CDC) STI treatment guidelines, key questions for management of genital herpes infection were developed with a panel of experts. To answer these questions, a systematic literature review was performed, with tables of evidence including articles that would change guidance assembled. These data were used to inform recommendations in the 2021 CDC STI treatment guidelines.
- Published
- 2022
24. Genital Herpes Simplex Virus Type 2 Suppression With Valacyclovir Is Not Associated With Changes in Nugent Score or Absolute Abundance of Key Vaginal Bacteria
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Tara M Babu, Sujatha Srinivasan, Amalia Magaret, Sean Proll, Helen Stankiewicz Karita, Jacqueline M Wallis, Stacy Selke, Dana Varon, Thepthara Pholsena, David Fredricks, Jeanne Marrazzo, Anna Wald, and Christine Johnston
- Subjects
Infectious Diseases ,Oncology - Abstract
BackgroundIn women, genital herpes simplex virus type 2 (HSV-2) infection is associated with increased risk for recurrent bacterial vaginosis (BV), but causal relationships are unclear.MethodsWomen with a self-reported history of BV and HSV-2 seropositivity self-collected vaginal and anogenital swabs for 2 nonconsecutive 28-day periods, in the absence or presence of valacyclovir suppressive therapy (500 mg daily). HSV polymerase chain reaction was performed on anogenital swabs; vaginal swabs were used for assessment of BV by Nugent score and quantification of vaginal microbiota. Days with BV, defined by Nugent score ≥7, were compared during the observational period and valacyclovir treatment.ResultsForty-one women collected swabs for a median of 28 days (range, 20–32 days) each study period. The HSV-2 shedding rate decreased from 109 of 1126 days (9.7%) presuppression to 6 of 1125 days (0.05%) during valacyclovir (rate ratio [RR], 0.06 [95% confidence interval {CI}, .02–.13]). BV occurred on 343 of 1103 days (31.1%) during observation and 302 of 1091 days (27.7%) during valacyclovir (RR, 0.90 [95% CI, .68–1.20]). The median per-person Nugent score was 3.8 during observation and 4.0 during valacyclovir. Average log10 concentrations of vaginal bacterial species did not change significantly during valacyclovir treatment.ConclusionsShort-term HSV-2 suppression with valacyclovir did not significantly affect the Nugent score or the vaginal microbiome despite potent suppression of HSV-2 shedding.
- Published
- 2023
25. Parent involvement in positive behaviour intervention and supports in Australia: teacher and parent/caregiver perspectives
- Author
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Michelle Rose, Mary Mooney, Christine Johnston, and Roberto H. Parada
- Subjects
Education - Abstract
Positive Behaviour Intervention and Supports (PBIS) is a framework for defining, teaching, and supporting appropriate social and academic behaviour in the school setting. This framework is widely implemented across the world, including Australia. Studies evaluating the effectiveness of PBIS confirm a relationship between implementation fidelity and student outcomes. Abundant literature highlights the significance of parent involvement (PI) on children’s social and academic outcomes. However, a consistently and surprisingly under researched component of PBIS is the involvement and influence of parents/caregivers. This article presents the findings of an original qualitative study using stakeholder interviews and artefact analysis to assess parent/caregiver involvement during PBIS implementation in two primary schools in South-West Sydney, Australia. These findings indicate that parent/caregiver involvement in PBIS implementation was interpreted differently by teachers and parents/caregivers and that there is potential for the development of improved methods to engage parents/caregivers more effectively in schools. Reframing parent/caregiver involvement in PBIS to address cultural sensitivities can progressively influence and stabilise this involvement to positively affect the sustainability, effectiveness and fidelity of PBIS. Limitations of the study together with recommendations for future practice are discussed.
- Published
- 2023
26. The Egyptian Nile: Human Transformation of an Ancient River
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Judith Bunbury, John P. Cooper, Richard Hoath, Salima Ikram, Christine Johnston, and Thomas Schneider
- Published
- 2023
27. 1463. Association between Herpes Simplex Virus Type 1 and the Risk of Alzheimer’s Disease
- Author
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Luke Liu, Nadine Jarousse, Christine Johnston, Simon P Fletcher, and Shahed Iqbal
- Subjects
Infectious Diseases ,Oncology - Abstract
Background There is significant unmet need of novel therapeutics for Alzheimer’s Disease (AD). A growing body of evidence suggests a role for herpesviruses in the development of AD and reduced risk of AD among patients receiving antivirals. We investigated the association between herpes simplex virus type 1 (HSV-1) diagnoses, antiviral use, and AD using real-world data. Methods In a matched case-control study, AD patients aged ≥ 50 years diagnosed between 2006 and 2021 were identified from IQVIA PharMetrics Plus® claims database using International Classification of Disease (ICD) codes (ICD 9 331.0; ICD 10 G30.x). Controls without any history of neurological disorders were matched in a 1:1 ratio with AD subjects on age, sex, region, database entry year, and healthcare visit numbers. HSV-1 diagnoses were identified using relevant ICD codes. Conditional logistic regression was used to evaluate the association between HSV-1 and AD. The association between antiviral use (e.g., acyclovir, famciclovir, valacyclovir) and AD was assessed by multivariate Cox proportional hazards model in patients with HSV-1 diagnosis. Results The study included 344,628 AD patient-control pairs. Most patients were female (65%) with a mean age of 73 (± 5) years. AD patients had more comorbidities (50% vs. 45% with ≥ 2 comorbidities) and shorter follow up time (median of 33 vs. 48 months) when compared to controls. History of HSV-1 diagnosis was present in 1507 (0.44%) AD patients vs. 823 (0.24%) controls. HSV-1 diagnosis was associated with AD (adjusted odds ratio [OR] 1.80; 95% confidence interval [CI] 1.65-1.96). In a stratified analysis, this association was more pronounced in the older age group (75+ years: OR 2.10, 95% CI 1.88-2.35; 71-74 years: OR 1.51, 95% CI 1.27-1.80; 50-70 years: OR 1.14, 95% CI 0.91-1.44). Patients with HSV-1 who used antivirals were less likely to have AD compared to those who did not use antivirals (adjusted hazard ratio 0.83, 95% CI 0.74-0.92). Similar results were observed when the analysis was extended to include all patients with AD-related dementia and matched controls. The association between herpes simplex virus type 1 (HSV-1) and Alzheimer’s Disease (AD)/AD-related Dementia(ADRD) Conclusion Findings from this large real-world data study is consistent with emerging literature on HSV-1 and risk of AD and the possible protective role of antiviral drugs. Disclosures Luke Liu, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Christine Johnston, MD, MPH, AbbVie: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant Simon P. Fletcher, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Shahed Iqbal, PhD, MBBS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds.
- Published
- 2022
28. 1948. Evaluation of a heterologous booster vaccine regimen: Pfizer-BioNTech BNT162b2 mRNA booster vaccine following priming with Novavax NVX-CoV2373
- Author
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Tara M Babu, R Scott McClelland, Christine Johnston, Stacy Selke, Dilpreet Singh, Jessica Moreno, Jina Taub, Morissa Pertik, Dana Varon, Thepthara Pholsena, Britt Murphy, Mark Drummond, Lindsey McClellan, Alyssa Braun, Matthew Seymour, Kirsten Hauge, Chris L McClurkan, Chloe Wilkens, Erin Goecker, Kerry J Laing, David M Koelle, Alexander L Greninger, and Anna Wald
- Subjects
Infectious Diseases ,Oncology - Abstract
Background In the United States, booster vaccines for persons 18 years and older were approved under Emergency Use Authorization (EUA) in September 2021. Waning immunity following SARS-CoV-2 primary vaccination series led to recommendations for booster vaccination. Emerging data suggest that providing boosters different from the primary series (heterologous vaccination) may provide a broader immune response than boosting with the same vaccine (homologous vaccination). CDC recommended the Pfizer-BioNTech BNT162b2 30-μg mRNA booster vaccine to clinical trial participants >6 months post study vaccines if not planned for boosting within the study. Methods We conducted an observational study of persons who received 2 doses of Novavax protein-based NVX-CoV2373 vaccine 21 days apart, in a Phase 3 clinical trial, and subsequently received a Pfizer BNT162b2 booster vaccine under EUA. Serologic assays, including the Roche anti-nucleocapsid (N) IgG and anti-Spike (S) IgG, were performed on blood collected pre-booster (D0) and on days 18 (D18) and 34 (D34) post-booster vaccine. The anti-S IgG geometric means (GMTs) were calculated over study time points. Wilcoxon signed rank test was performed to compare anti-S IgG response between D0 and D18 and D0 and D34. Results Of 26 participants enrolled, 16 (57%) were women; the median age was 47 years (range 29-67). Roche anti-N antibodies were negative at all visits. Time from second NVX-CoV2373 vaccine to Pfizer BNT162b2 booster was a median of 10.4 months in 54% of participants and 7 months in 46% of participants. Anti-S IgG GMTs were 222 BAU/ml D0, 24,723 BAU/ml D18, and 24,584 BAU/ml D34 (p< 0.0001 for comparisons of D0 with D18 & D34). Overall, participants tolerated the booster vaccine without significant adverse events. Cell mediated immunity and D614G pseudovirus neutralizing antibody assays are in progress. Figure 1.Anti-S IgG titers pre and post-booster vaccine 16 participants included with all 3-time study time points for comparison. Conclusion Two doses of NVX-CoV2373 vaccine followed by the Pfizer BNT162b2 booster vaccine resulted in ∼100-fold increase in anti-S IgG against SARS-CoV-2. No participant had evidence of prior SARS-CoV-2 infection by anti-N IgG. Two doses of NVX-CoV2373 vaccine followed by one dose of Pfizer BNT162b2 vaccine is an effective and well-tolerated regimen for boosting anti-S IgG against SARS-CoV-2. Disclosures Christine Johnston, MD, MPH, AbbVie: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant Kerry J. Laing, PhD, Curevo Vaccine: Advisor/Consultant|MaxHealth Biotechnology: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support David M. Koelle, MD, Curevo Vaccines: Advisor/Consultant|MaxHealth LLC: Advisor/Consultant|Oxford Immunotec: gift of reagents|Sanofi: Grant/Research Support|Sensei: Grant/Research Support Alexander L. Greninger, MD, PhD, Abbott: Contract Testing|Cepheid: Contract Testing|Gilead: Grant/Research Support|Gilead: Contract Testing|Hologic: Contract Testing|Merck: Grant/Research Support|Novavax: Contract Testing|Pfizer: Contract Testing Anna Wald, MD, MPH, Aicuris: Advisor/Consultant|Auritec: Advisor/Consultant|Crozet: Advisor/Consultant|DXNow: Advisor/Consultant|GSK: Grant/Research Support|Merck: Advisor/Consultant|sanofi: Grant/Research Support|VIR: Advisor/Consultant|X-Vax: Advisor/Consultant.
- Published
- 2022
29. Sexually Transmitted Infections Treatment Guidelines, 2021
- Author
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Ina U. Park, Christine Johnston, Gail Bolan, Jonathan M. Zenilman, Kimberly A. Workowski, Christina A. Muzny, Philip A. Chan, Hilary Reno, and Laura H. Bachmann
- Subjects
medicine.medical_specialty ,Health (social science) ,Epidemiology ,Health, Toxicology and Mutagenesis ,Sexually Transmitted Diseases ,medicine.disease_cause ,Men who have sex with men ,Health Information Management ,Recommendations and Reports ,Pelvic inflammatory disease ,medicine ,Humans ,biology ,business.industry ,General Medicine ,Hepatitis C ,medicine.disease ,biology.organism_classification ,United States ,Family medicine ,Neisseria gonorrhoeae ,Trichomonas vaginalis ,Centers for Disease Control and Prevention, U.S ,Bacterial vaginosis ,business ,Chlamydia trachomatis ,Mycoplasma genitalium - Abstract
Summary These guidelines for the treatment of persons who have or are at risk for sexually transmitted infections (STIs) were updated by CDC after consultation with professionals knowledgeable in the field of STIs who met in Atlanta, Georgia, June 11–14, 2019. The information in this report updates the 2015 guidelines. These guidelines discuss 1) updated recommendations for treatment of Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis; 2) addition of metronidazole to the recommended treatment regimen for pelvic inflammatory disease; 3) alternative treatment options for bacterial vaginosis; 4) management of Mycoplasma genitalium; 5) human papillomavirus vaccine recommendations and counseling messages; 6) expanded risk factors for syphilis testing among pregnant women; 7) one-time testing for hepatitis C infection; 8) evaluation of men who have sex with men after sexual assault; and 9) two-step testing for serologic diagnosis of genital herpes simplex virus. Physicians and other health care providers can use these guidelines to assist in prevention and treatment of STIs.
- Published
- 2021
30. The viral hypothesis: how herpesviruses may contribute to Alzheimer’s disease
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Ben Readhead, Martin Darvas, Christine Johnston, David M. Koelle, Tain Luquez, Cory C. Funk, and Michael Wainberg
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0301 basic medicine ,Amyloid beta ,Population ,Context (language use) ,Disease ,Pathogenesis ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,Animals ,Medicine ,education ,Molecular Biology ,Herpesviridae ,Neuroinflammation ,education.field_of_study ,Amyloid beta-Peptides ,biology ,business.industry ,Disease Models, Animal ,Psychiatry and Mental health ,Chronic infection ,030104 developmental biology ,Perspective ,Immunology ,biology.protein ,Etiology ,business ,030217 neurology & neurosurgery ,Neuroscience - Abstract
The hypothesis that infectious agents, particularly herpesviruses, contribute to Alzheimer’s disease (AD) pathogenesis has been investigated for decades but has long engendered controversy. In the past 3 years, several studies in mouse models, human tissue models, and population cohorts have reignited interest in this hypothesis. Collectively, these studies suggest that many of the hallmarks of AD, like amyloid beta production and neuroinflammation, can arise as a protective response to acute infection that becomes maladaptive in the case of chronic infection. We place this work in its historical context and explore its etiological implications.
- Published
- 2021
31. Leveraging E-Learning Infrastructure in Times of Rapid Change: Use of the National Sexually Transmitted Diseases Curriculum in the Era of COVID-19
- Author
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Karin M. Bauer, Jehan Z Budak, Christine Johnston, David H. Spach, and Maria A. Corcorran
- Subjects
Microbiology (medical) ,2019-20 coronavirus outbreak ,Medical education ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,E-learning (theory) ,education ,Public Health, Environmental and Occupational Health ,Sexually Transmitted Diseases ,COVID-19 ,Dermatology ,Note ,Infectious Diseases ,Pandemic ,Medicine ,Humans ,Training needs ,Curriculum ,Learning group ,business ,Pandemics ,Computer-Assisted Instruction - Abstract
Increases in new National Sexually Transmitted Diseases Curriculum registrants and learning groups during the COVID-19 pandemic demonstrate that e-learning platforms can be leveraged to meet rapidly changing training needs., The National Sexually Transmitted Diseases Curriculum is an e-learning platform. New registrations and learning group creations in March to April 2020 were compared with previous 12-month data. Substantial increases in registrations and learning groups demonstrate that the National Sexually Transmitted Diseases Curriculum was successfully leveraged to meet rapidly shifting training needs due to the COVID-19 pandemic.
- Published
- 2021
32. Characteristics of the Audience Reached by the National Network of Sexually Transmitted Disease Clinical Prevention Training Centers and Correlation With Sexually Transmitted Infection Rates, 2015 to 2020
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Benjamin C, Hauschild, Helen C, Burnside, Barbara A, Gray, Christine, Johnston, Natalie, Neu, Ina U, Park, Hilary E L, Reno, Anne, Rompalo, Nicholas, Van Wagoner, Karen A, Wendel, Alexandra, Coor, Erin, Tromble, and Cornelis A, Rietmeijer
- Subjects
Sexually Transmitted Diseases ,Humans ,Public Health ,United States - Abstract
The National Network of Sexually Transmitted Disease Clinical Prevention Training Centers (NNPTC) trains clinical providers to diagnose and treat sexually transmitted infections (STIs) in the United States. The purpose of this study was to examine the demographics of clinical providers and to correlate the number of training episodes with STI rates at the county level.Registration data were collected between April 1, 2015, and March 31, 2020, in a custom Learning Management System from clinical providers taking NNPTC training. Using the 2018 STI surveillance data, counties were divided into quartiles based on reportable STI case rates and the number of county-level training events was compared per quartile. Univariate and multivariate analyses were conducted in IBM SPSS Statistics 23 (Armonk, NY) and SAS Enterprise Guide 7.1 (Cary, NC).From 2015 to 2020, the NNPTC trained 21,327 individuals, predominantly in the nursing professions and working in a public health environment. In multivariate analysis, the number of training events was significantly associated with higher STI rates at the county level (P0.0001) and the state where a prevention training center is located (P0001).The analysis suggests that NNPTC trainings are reaching the clinical providers working in geographic areas with higher STI rates.
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- 2022
33. Comparison of Racial, Ethnic, and Geographic Location Diversity of Participants Enrolled in Clinic-Based vs 2 Remote COVID-19 Clinical Trials
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Jenell Stewart, Meighan L. Krows, Torin T. Schaafsma, Kate B. Heller, Elizabeth R. Brown, Jim Boonyaratanakornkit, Clare E. Brown, Hannah Leingang, Caroline Liou, Anna Bershteyn, Mark D. Schwartz, Vaidehi Agrawal, DeAnna Friedman-Klabanoff, Stephen Eustace, Helen C. Stankiewicz Karita, Michael K. Paasche-Orlow, Patricia Kissinger, Sybil G. Hosek, Helen Y. Chu, Connie Celum, Jared M. Baeten, Anna Wald, Christine Johnston, and Ruanne V. Barnabas
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Adult ,Cohort Studies ,Male ,SARS-CoV-2 ,Patient Selection ,COVID-19 ,Humans ,Female ,General Medicine ,Middle Aged ,Pandemics ,Randomized Controlled Trials as Topic - Abstract
Racial and ethnic diversity among study participants is associated with improved generalizability of clinical trial results and may address inequities in evidence that informs public health strategies. Novel strategies are needed for equitable access and recruitment of diverse clinical trial populations.To investigate demographic and geographical location data for participants in 2 remote COVID-19 clinical trials with online recruitment and compare with those of a contemporaneous clinic-based COVID-19 study.This cohort study was conducted using data from 3 completed, prospective randomized clinical trials conducted at the same time: 2 remotely conducted studies (the Early Treatment Study and Hydroxychloroquine COVID-19 Postexposure Prophylaxis [PEP] Study) and 1 clinic-based study of convalescent plasma (the Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study). Data were collected from March to August 2020 with 1 to 28 days of participant follow-up. All studies had clinical sites in Seattle, Washington; the 2 remote trials also had collaborating sites in New York, New York; Syracuse, New York; Baltimore, Maryland; Boston, Massachusetts; Chicago, Illinois; New Orleans, Louisiana; and Los Angeles, California. Two remote trials with inclusive social media strategies enrolled 929 participants with recent SARS-CoV-2 exposure (Hydroxychloroquine COVID-19 PEP Trial) and 231 participants with COVID-19 infection (Early Treatment Study); the clinic-based Expanded Access to Convalescent Plasma for the Treatment of Patients With COVID-19 study enrolled 250 participants with recent COVID-19 infection. Data were analyzed from April to August 2021.Remote trials used inclusive social media strategies and clinician referral for recruitment and telehealth, courier deliveries, and self-collected nasal swabs for remotely conducted study visits. For the clinic-based study, participants were recruited via clinician referral and attended in-person visits.Google Analytics data were used to measure online participant engagement and recruitment. Participant demographics and geographical location data from remote trials were pooled and compared with those of the clinic-based study. Statistical comparison of demographic data was limited to participants with COVID infections (ie, those in the remotely conducted Early Treatment Study vs those in the clinic-based study) to improve accuracy of comparison given that the Hydroxychloroquine COVID-19 PEP Trial enrolled participants with COVID-19 exposures and thus had different enrollment criteria.A total of 1410 participants were included. Among 1160 participants in remote trials and 250 participants in the clinic-based trial, the mean (range) age of participants was 39 (18-80) years vs 50 (19-79) years and 676 individuals (58.3%) vs 131 individuals (52.4%) reported female sex. The Early Treatment Study with inclusive social media strategies enrolled 231 participants in 41 US states with increased rates of racial, ethnic, and geographic diversity compared with participants in the clinic-based study. Among 228 participants in the remotely conducted Early Treatment Study with race data vs participants in the clinic-based study, 39 individuals (17.1%) vs 1 individual (0.4%) identified as Alaska Native or American Indian, 11 individuals (4.8%) vs 22 individuals (8.8%) identified as Asian, 26 individuals (11.4%) vs 4 individuals (1.6%) identified as Black, 3 individuals (1.3%) vs 1 individual identified as Native Hawaiian or Pacific Islander, 117 individuals (51.3%) vs 214 individuals (85.6%) identified as White, and 32 individuals (14.0%) vs 8 individuals (3.2%) identified as other race (P .001). Among 230 individuals in the Early Treatment Study vs 236 individuals in the clinic-based trial with ethnicity data, 71 individuals (30.9%) vs 11 individuals (4.7%) identified as Hispanic or Latinx (P.001). There were 29 individuals in the Early Treatment Study with nonurban residences (ie, rural, small town, or peri-urban; 12.6%) vs 6 of 248 individuals in the clinic-based trial with residence data (2.4%) (P .001). In remote trial online recruitment, the highest engagement was with advertisements on social media platforms; among 125 147 unique users with age demographics who clicked on online recruitment advertisements, 84 188 individuals (67.3%) engaged via Facebook.These findings suggest that remote clinical trials with online advertising may be considered as a strategy to improve diversity among clinical trial participants.
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- 2022
34. Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine
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Emily S. Ford, Alvason Li, Christine Johnston, Lichun Dong, Kurt Diem, Lichen Jing, Kerry J. Laing, Alexis Klock, Krithi Basu, Mariliis Ott, Jim Tartaglia, Sanjay Gurunathan, Jack L. Reid, Matyas Ecsedi, Aude G. Chapuis, Meei-Li Huang, Amalia S. Magaret, Jia Zhu, David M. Koelle, and Lawrence Corey
- Abstract
The skin at the site of HSV-2 reactivation is enriched for HSV-2 specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells we studied skin biopsies and HSV-2-reactive CD4+ T cells from peripheral blood mononuclear cells (PBMCs) by T-cell receptor (TCR) sequencing before and after vaccination with a replication-incompetent whole virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2-reactive CD4+ T cell sequences from PBMCs increased from a median of 0.03% (range 0-0.09%) to 0.6% (range 0-1.3%) of the total skin TCR repertoire after the first vaccine dose. We found sustained expansion after vaccination in unique, skin-based T-cell clonotypes that were not detected in HSV-2-reactive CD4+ T cells isolated from PBMCs. While detection of skin clonotypes in the blood was related to abundance in the skin it was not related to expansion after vaccination. In one participant a switch in immunodominance was observed after vaccination with the emergence of a newly dominant TCRa/b pair in skin that was not detected in blood. We confirmed that the newly dominant clonotype was derived from an HSV-specific CD4+ T cell by creation of a synthetic TCR in a Jurkat-based cell line with a NR4A1-mNeonGreen reporter system. Our data indicate that the skin in areas of HSV-2 reactivation possesses an oligoclonal TCR repertoire that is distinct from the circulation with prominent clonotypes infrequently detected in the circulation by standard methods. Defining the influence of therapeutic vaccination on the HSV-2-specific TCR repertoire requires tissue-based evaluation.
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- 2022
35. Homologous and Heterologous Covid-19 Booster Vaccinations
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Robert L, Atmar, Kirsten E, Lyke, Meagan E, Deming, Lisa A, Jackson, Angela R, Branche, Hana M, El Sahly, Christina A, Rostad, Judith M, Martin, Christine, Johnston, Richard E, Rupp, Mark J, Mulligan, Rebecca C, Brady, Robert W, Frenck, Martín, Bäcker, Angelica C, Kottkamp, Tara M, Babu, Kumaravel, Rajakumar, Srilatha, Edupuganti, David, Dobrzynski, Rhea N, Coler, Christine M, Posavad, Janet I, Archer, Sonja, Crandon, Seema U, Nayak, Daniel, Szydlo, Jillian A, Zemanek, Clara P, Dominguez Islas, Elizabeth R, Brown, Mehul S, Suthar, M Juliana, McElrath, Adrian B, McDermott, Sarah E, O'Connell, David C, Montefiori, Amanda, Eaton, Kathleen M, Neuzil, David S, Stephens, Paul C, Roberts, John H, Beigel, and Todd, Haight
- Subjects
Adult ,Aged, 80 and over ,Male ,COVID-19 Vaccines ,Ad26COVS1 ,SARS-CoV-2 ,T-Lymphocytes ,Immunization, Secondary ,General Medicine ,Middle Aged ,Antibodies, Viral ,Antibodies, Neutralizing ,Injections, Intramuscular ,Immunogenicity, Vaccine ,Spike Glycoprotein, Coronavirus ,Humans ,Female ,BNT162 Vaccine ,2019-nCoV Vaccine mRNA-1273 ,Aged - Abstract
Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients.In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 μg, Ad26.COV2.S (JohnsonJohnson-Janssen) at a dose of 5×10Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients.Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).
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- 2022
36. Trajectory of Viral RNA Load Among Persons With Incident SARS-CoV-2 G614 Infection (Wuhan Strain) in Association With COVID-19 Symptom Onset and Severity
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Helen C. Stankiewicz Karita, Tracy Q. Dong, Christine Johnston, Kathleen M. Neuzil, Michael K. Paasche-Orlow, Patricia J. Kissinger, Anna Bershteyn, Lorna E. Thorpe, Meagan Deming, Angelica Kottkamp, Miriam Laufer, Raphael J. Landovitz, Alfred Luk, Risa Hoffman, Pavitra Roychoudhury, Craig A. Magaret, Alexander L. Greninger, Meei-Li Huang, Keith R. Jerome, Mark Wener, Connie Celum, Helen Y. Chu, Jared M. Baeten, Anna Wald, Ruanne V. Barnabas, and Elizabeth R. Brown
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Adult ,Male ,SARS-CoV-2 ,viruses ,Incidence ,Research ,COVID-19 ,General Medicine ,Middle Aged ,Viral Load ,Polymerase Chain Reaction ,Severity of Illness Index ,Virus Shedding ,Online Only ,Infectious Diseases ,Molecular Diagnostic Techniques ,Humans ,RNA, Viral ,Female ,Serologic Tests ,Longitudinal Studies ,Prospective Studies ,Original Investigation - Abstract
Key Points Question What are the characteristics of SARS-CoV-2 G614 viral shedding in incident infections in association with COVID-19 symptom onset and severity? Findings In a cohort study of persons who tested positive for SARS-CoV-2 after recent exposure, viral RNA trajectory was characterized by a rapid peak followed by slower decay. Peak viral load correlated positively with symptom severity and generally occurred within 1 day of symptom onset if the patient was symptomatic. Meaning A detailed description of the SARS-CoV-2 G614 viral shedding trajectory serves as a baseline for comparison with new viral variants of concern and informs models to plan clinical trials to end the pandemic., Importance The SARS-CoV-2 viral trajectory has not been well characterized in incident infections. These data are needed to inform natural history, prevention practices, and therapeutic development. Objective To characterize early SARS-CoV-2 viral RNA load (hereafter referred to as viral load) in individuals with incident infections in association with COVID-19 symptom onset and severity. Design, Setting, and Participants This prospective cohort study was a secondary data analysis of a remotely conducted study that enrolled 829 asymptomatic community-based participants recently exposed (, This cohort study characterizes early SARS-CoV-2 viral RNA load in individuals with incident infections in association with COVID-19 symptom onset and severity.
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- 2022
37. Rapid Decline in Vaccine-Boosted Neutralizing Antibodies Against SARS-CoV-2 Omicron Variant
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Kirsten E. Lyke, Robert L. Atmar, Clara Dominguez Islas, Christine M. Posavad, Daniel Szydlo, Rahul PaulChourdhury, Meagan E. Deming, Amanda Eaton, Lisa A. Jackson, Angela Ramon Branche, Hana M. El Sahly, Christina Rostad, Judith M. Martin, Christine Johnston, Richard Rupp, Mark J. Mulligan, Rebecca C. Brady, Robert Frenck, Martin Bäcker, Angelica Kottkamp, Tara M. Babu, Kumaravel Rajakumar, Srilatha Edupuganti, David Dobrzynski, Rhea N. Coler, Janet I. Archer, Sonja Crandon, Jillian A. Zemanek, Elizabeth R. Brown, Kathleen M. Neuzil, David S. Stephens, Diane J. Post, Seema U. Nayak, Mehul Suthar, Paul C. Roberts, John H. Beigel, and David C. Montefiori
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
38. Optimising treatments for sexually transmitted infections: surveillance, pharmacokinetics and pharmacodynamics, therapeutic strategies, and molecular resistance prediction
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Magnus Unemo, Christine Johnston, Edward W. Hook, Arlene C. Seña, Kimberly A. Workowski, Teodora Wi, Laura H. Bachmann, George L. Drusano, and Jane S Hocking
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0301 basic medicine ,medicine.medical_specialty ,030106 microbiology ,Drug Resistance ,Sexually Transmitted Diseases ,Drug resistance ,urologic and male genital diseases ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Antibiotic resistance ,Anti-Infective Agents ,Humans ,Medicine ,030212 general & internal medicine ,Intensive care medicine ,biology ,business.industry ,Transmission (medicine) ,Public health ,biology.organism_classification ,Antimicrobial ,female genital diseases and pregnancy complications ,Infectious Diseases ,Population Surveillance ,Neisseria gonorrhoeae ,Trichomonas vaginalis ,business ,Mycoplasma genitalium - Abstract
Progressive antimicrobial resistance in Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis has created a pressing need for treatment optimisations for sexually transmitted infections (STIs). In this Review, we aim to highlight urgent needs in global STI management, including: (1) improved surveillance to monitor antimicrobial resistance and clinical outcomes; (2) systematic pharmacokinetic and pharmacodynamic evaluations to ensure resistance suppression and bacterial eradication at all sites of infection; (3) development of novel, affordable antimicrobials; and (4) advancements in new molecular and point-of-care tests to detect antimicrobial resistance determinants. Antimicrobial resistance among STIs is a global public health crisis. Continuous efforts to develop novel antimicrobials will be essential, in addition to other public health interventions to reduce the global STI burden. Apart from prevention through safer sexual practices, the development of STI vaccines to prevent transmission is a crucial research priority.
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- 2020
39. Evaluation of the National Sexually Transmitted Disease Curriculum: Reach, Utilization, and Engagement
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Christine Johnston, Jeanne M. Marrazzo, Kenton T. Unruh, Andrew Karpenko, David H. Spach, Gretchen Snoeyenbos Newman, Karin M. Bauer, and Kimberly A. Workowski
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Microbiology (medical) ,Sexually transmitted disease ,medicine.medical_specialty ,Health Personnel ,Sexually Transmitted Diseases ,Dermatology ,Session (web analytics) ,Likert scale ,Education, Distance ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,030212 general & internal medicine ,Duration (project management) ,Location ,Curriculum ,Internet ,030505 public health ,business.industry ,Public Health, Environmental and Occupational Health ,United States ,Infectious Diseases ,Analytics ,Family medicine ,Advanced Practice Nurses ,0305 other medical science ,business ,Computer-Assisted Instruction - Abstract
BACKGROUND With increasing rates of sexually transmitted infections in the United States, there is a critical need to educate health professionals on the prevention, diagnosis, and treatment of sexually transmitted infections. The National Sexually Transmitted Disease Curriculum (NSTDC, https://www.std.uw.edu) is a free, online curriculum, funded by the Centers for Disease Control and Prevention. The purpose of this article is to evaluate the reach, utilization, and engagement of users with the curriculum. METHODS Data on NSTDC utilization was collected for 24 months after the February 1, 2017 launch. For all users, Google Analytics was used to determine total number of users, geographic location, age and sex, and average session duration. For registered users, additional data analysis included work-role, demographics, and completion of self-study modules, check-on-learning questions, and question banks. User satisfaction was measured on a 5-point Likert scale. RESULTS During the evaluation period, 136,270 individual users accessed the NSTDC, including 24,652 registered users. Among all registered users, 10,660 (43.2%) were registered nurses, 2810 (11.4%) physicians, 4942 (20.1%) Advanced Practice Nurses and Physician Assistants, and 6213 (25.2%) nonclinicians. Among registered users, 18,533 (75.2%) completed at least 1 module, 7898 (32.0%) completed all 7 modules, and 19,804 (80.4%) answered optional check-on-learning questions. Median satisfaction with the content was (5) very satisfied (interquartile range, 4-5). CONCLUSIONS The NSTDC is a free, guideline-based, online curriculum with novel dual functionality that has achieved extensive reach with a broad array of health professionals who engage deeply with the material. The wide usage of NSTDC demonstrates the need for high-quality, unbiased, free content in user-focused formats.
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- 2020
40. Time Trends in First-Episode Genital Herpes Simplex Virus Infections in an Urban Sexually Transmitted Disease Clinic
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Anna Wald, Julia C. Dombrowski, Christine Johnston, Amalia Magaret, David A. Katz, and Nazila M Dabestani
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Adult ,Male ,Washington ,Microbiology (medical) ,Sexually transmitted disease ,medicine.medical_specialty ,Herpesvirus 2, Human ,Sexual Behavior ,Population ,Prevalence ,Herpesvirus 1, Human ,Dermatology ,Men who have sex with men ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Epidemiology ,medicine ,Humans ,Sex organ ,030212 general & internal medicine ,education ,First episode ,education.field_of_study ,Herpes Genitalis ,030505 public health ,business.industry ,Urban Health ,Public Health, Environmental and Occupational Health ,Infectious Diseases ,Relative risk ,Female ,0305 other medical science ,business - Abstract
BACKGROUND Genital herpes simplex virus type 1 (HSV-1) has emerged as the leading cause of first-episode genital herpes among specific populations in the United States, such as adolescents, young adult women, and men who have sex with men (MSM). We examined trends in the etiology of first-episode genital herpes diagnoses over time in a sexually transmitted disease (STD) clinic population. METHODS Using an electronic database, we identified persons diagnosed as having first-episode genital herpes at Public Health - Seattle & King County STD Clinic from 1993 to 2014 and compared risk factors for genital HSV-1 versus herpes simplex virus type 2 (HSV-2) infection. RESULTS Of 52,030 patients with genital ulcers, 3065 (6.15%) had first-episode genital herpes infection: 1022 (33.3%) with HSV-1 and 2043 (67.7%) with HSV-2. Overall, 1154 (37.7%) were women, the median age was 28 years (interquartile range, 24-36 years), 1875 (61.2%) patients were white, and 353 (11.5%) were MSM. The number of patients diagnosed as having first-episode genital HSV-2 declined on average by 5.5 persons per year, from 208 in 1993 to 35 in 2014 (change of -5.6 per year; 95% confidence interval [CI], -6.9 to -4.1), whereas HSV-1 diagnoses remained stable at approximately 50 per year (change of 0.2; 95% CI, -0.4 to 0.9). In a multivariate model, persons diagnosed as having first-episode genital HSV-1 rather than genital HSV-2 infection were more likely to be younger (age
- Published
- 2019
41. Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report
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Robert L, Atmar, Kirsten E, Lyke, Meagan E, Deming, Lisa A, Jackson, Angela R, Branche, Hana M, El Sahly, Christina A, Rostad, Judith M, Martin, Christine, Johnston, Richard E, Rupp, Mark J, Mulligan, Rebecca C, Brady, Robert W, Frenck, Martín, Bäcker, Angelica C, Kottkamp, Tara M, Babu, Kumaravel, Rajakumar, Srilatha, Edupuganti, David, Dobryzynski, Christine M, Posavad, Janet I, Archer, Sonja, Crandon, Seema U, Nayak, Daniel, Szydlo, Jillian, Zemanek, Clara P Dominguez, Islas, Elizabeth R, Brown, Mehul S, Suthar, M Juliana, McElrath, Adrian B, McDermott, Sarah E, O'Connell, David C, Montefiori, Amanda, Eaton, Kathleen M, Neuzil, David S, Stephens, Paul C, Roberts, and John H, Beigel
- Subjects
Reactogenicity ,Booster (rocketry) ,biology ,business.industry ,SARS-CoV-2 ,Immunogenicity ,mRNA ,Heterologous ,Booster dose ,Virology ,Article ,Booster ,Vaccination ,Regimen ,antibody ,biology.protein ,Medicine ,business ,Neutralizing antibody ,Covid-19 ,Vaccine ,recombinant adenovirus - Abstract
BackgroundWhile Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen.MethodsIn this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-μg, Janssen Ad26.COV2.S 5×1010 virus particles, or Pfizer-BioNTech BNT162b2 30-μg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29.Results458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations.ConclusionHomologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.(Funded by National Institute of Allergy and Infectious Diseases; Clinical Trials.gov number, NCT04889209)
- Published
- 2021
42. Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection
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Christine, Johnston, Amalia, Magaret, Hyunju, Son, Michael, Stern, Molly, Rathbun, Daniel, Renner, Moriah, Szpara, Sarah, Gunby, Mariliis, Ott, Lichen, Jing, Victoria L, Campbell, Meei-Li, Huang, Stacy, Selke, Keith R, Jerome, David M, Koelle, and Anna, Wald
- Subjects
Adult ,Male ,Herpes Genitalis ,Herpesvirus 2, Human ,HIV Infections ,Herpes Simplex ,Herpesvirus 1, Human ,General Medicine ,Middle Aged ,Virus Shedding ,Pregnancy ,Humans ,Female ,Prospective Studies ,Genitalia - Abstract
ImportanceHerpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.ObjectiveTo inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized.Design, Setting, and ParticipantsProspective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment.ExposuresFirst-episode genital HSV-1 infection.Main Outcomes and MeasuresGenital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot.ResultsAmong the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period.Conclusions and RelevanceGenital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection.
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- 2022
43. Trajectory of viral load in a prospective population-based cohort with incident SARS-CoV-2 G614 infection
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Christine Johnston, Elizabeth R. Brown, Craig Magaret, Helen C. Stankiewicz Karita, Patricia Kissinger, Meei-Li Huang, Connie Celum, Anna Wald, Michael K. Paasche-Orlow, Mark H. Wener, Alfred Luk, Anna Bershteyn, Jared M. Baeten, Pavitra Roychoudhury, Angelica Kottkamp, Kathleen M. Neuzil, Helen Y. Chu, Risa M Hoffman, Alexander L. Greninger, Raphael J. Landovitz, Meagan E. Deming, Miriam K. Laufer, Lorna E. Thorpe, Tracy Qi Dong, Keith R. Jerome, and Ruanne V. Barnabas
- Subjects
medicine.medical_specialty ,business.industry ,Transmission (medicine) ,Asymptomatic ,Virus ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Viral shedding ,medicine.symptom ,business ,Prospective cohort study ,Viral load ,Cohort study - Abstract
ImportanceSARS-CoV-2 viral trajectory has not been well-characterized in documented incident infections. These data will inform SARS-CoV-2 natural history, transmission dynamics, prevention practices, and therapeutic development.ObjectiveTo prospectively characterize early SARS-CoV-2 viral shedding in persons with incident infection.DesignProspective cohort study.SettingSecondary data analysis from a multicenter study in the U.S.ParticipantsThe samples derived from a randomized controlled trial of 829 community-based asymptomatic participants recently exposed (ExposureLaboratory-confirmed SARS-CoV-2 infection.Main outcomes and measuresThe observed SARS-CoV-2 viral shedding characteristics were summarized and shedding trajectories were examined using a piece-wise linear mixed-effects modeling. Whole viral genome sequencing was performed on samples with cycle threshold (Ct)ResultsNinety-seven persons (57% women, median age 37-years) developed incident infections during 14-days of follow-up. Two-hundred fifteen sequenced samples were assigned to 15 lineages that belonged to the G614 variant. Forty-two (43%), 18(19%), and 31(32%) participants had viral shedding for 1 day, 2-6 days, and ≥7 days, with median peak viral load Ct of 38.5, 36.7, and 18.3, respectively. Six (6%) participants had 1–6 days of observed viral shedding with censored duration. The peak average viral load was observed on day 3 of viral shedding. The average Ct value was lower, indicating higher viral load, in persons reporting COVID-19 symptoms than asymptomatic. Using the statistical model, the median time from shedding onset to peak viral load was 1.4 days followed by a median of 9.7 days before clearance.Conclusions and RelevanceIncident SARS-CoV-2 G614 infection resulted in a rapid viral load peak followed by slower decay and positive correlation between peak viral load and shedding duration; duration of shedding was heterogeneous. This longitudinal evaluation of the SARS-CoV-2 G614 variant with frequent molecular testing may serve as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.KEY POINTSQuestionWhat are the early SARS-CoV-2 G614 viral shedding characteristics in persons with incident infection?FindingsIn this prospective cohort of 97 community-based participants who collected daily mid-turbinate swabs for SARS-CoV-2 detection after recent exposure to SARS-CoV-2, viral trajectory was characterized by a rapid peak followed by slower decay. Peak viral load correlated positively with symptoms. The duration of shedding was heterogeneous.MeaningA detailed description of the SARS-CoV-2 G614 viral shedding trajectory serves as baseline for comparison to new viral variants of concern and inform models for the planning of clinical trials and transmission dynamics to end this pandemic.
- Published
- 2021
44. Examining the dynamics of Epstein-Barr virus shedding in the tonsils and the impact of HIV-1 coinfection on daily saliva viral loads
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Christine Johnston, Meei-Li Huang, Fred Okuku, Joshua T. Schiffer, Corey Casper, Anna Wald, Lawrence Corey, Jackson Orem, Habibur Rahman, Soren Gantt, Daniel Coombs, and Catherine M. Byrne
- Subjects
0301 basic medicine ,RNA viruses ,Male ,Saliva ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,B Cells ,Physiology ,Palatine Tonsil ,HIV Infections ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Cohort Studies ,White Blood Cells ,0302 clinical medicine ,Medical Conditions ,Immunodeficiency Viruses ,Animal Cells ,Medicine and Health Sciences ,Medicine ,Uganda ,Biology (General) ,B-Lymphocytes ,Immunity, Cellular ,Ecology ,T Cells ,Coinfection ,Viral Load ,Middle Aged ,Tonsils ,3. Good health ,Body Fluids ,Virus Shedding ,Infectious Diseases ,Computational Theory and Mathematics ,Medical Microbiology ,Modeling and Simulation ,Viral Pathogens ,Cohort ,Viruses ,Female ,Pathogens ,Anatomy ,Cellular Types ,Viral load ,Research Article ,Adult ,Herpesviruses ,Adolescent ,QH301-705.5 ,Immune Cells ,Immunology ,Microbiology ,Models, Biological ,Virus ,Throat ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Young Adult ,Immune system ,Acquired immunodeficiency syndrome (AIDS) ,Virology ,Retroviruses ,Genetics ,Epstein-Barr virus ,Humans ,Antibody-Producing Cells ,Molecular Biology ,Microbial Pathogens ,Ecology, Evolution, Behavior and Systematics ,Stochastic Processes ,Blood Cells ,business.industry ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Computational Biology ,Cell Biology ,medicine.disease ,Epstein–Barr virus ,030104 developmental biology ,Co-Infections ,HIV-1 ,business ,DNA viruses ,Viral Transmission and Infection ,Neck ,030215 immunology - Abstract
Epstein-Barr virus (EBV) is transmitted by saliva and is a major cause of cancer, particularly in people living with HIV/AIDS. Here, we describe the frequency and quantity of EBV detection in the saliva of Ugandan adults with and without HIV-1 infection and use these data to develop a novel mathematical model of EBV infection in the tonsils. Eligible cohort participants were not taking antiviral medications, and those with HIV-1 infection had a CD4 count >200 cells/mm3. Over a 4-week period, participants provided daily oral swabs that we analysed for the presence and quantity of EBV. Compared with HIV-1 uninfected participants, HIV-1 coinfected participants had an increased risk of EBV detection in their saliva (IRR = 1.27, 95% CI = 1.10–1.47) and higher viral loads in positive samples. We used these data to develop a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and immune response within the tonsillar epithelium to analyse potential factors that may cause EBV infection to be more severe in HIV-1 coinfected participants. The model, fit using Approximate Bayesian Computation, showed high fidelity to daily oral shedding data and matched key summary statistics. When evaluating how model parameters differed among participants with and without HIV-1 coinfection, results suggest HIV-1 coinfected individuals have higher rates of B cell reactivation, which can seed new infection in the tonsils and lower rates of an EBV-specific immune response. Subsequently, both these traits may explain higher and more frequent EBV detection in the saliva of HIV-1 coinfected individuals., Author summary Epstein-Barr virus (EBV) is a ubiquitous infection worldwide associated with the development of several kinds of cancer, including B cell lymphoma and nasopharyngeal carcinoma. Rates of EBV replication and disease are higher in individuals who are coinfected with HIV-1. HIV-1 infection is associated with increased B cell activation as well as immunodeficiency resulting from loss of T cells; however, whether these factors contribute to higher rates of EBV replication during coinfection, and by how much, has remained unknown. We analysed oral EBV shedding data from a cohort of Ugandan adults taken at multiple time points and found that participants coinfected with HIV-1 maintained higher quantities of EBV in their saliva. To better understand this finding, we developed a mathematical model to describe the dynamics of EBV infection within the tonsils. By rigorously matching our model to our participant data, we determined that both high rates of infected B cell activation and worse cellular immune control of EBV may cause higher EBV loads in saliva during HIV-1 coinfection. These results help explain the impact of HIV-1 on EBV and suggest potential therapeutic targets to prevent EBV-related malignancy in people who are coinfected with HIV-1.
- Published
- 2021
45. Diabetes care in the early primary school setting: narratives of Australian mothers
- Author
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Christine Johnston, Stacy Blythe, Anne Marks, and Nathan J. Wilson
- Subjects
Advanced and Specialized Nursing ,Type 1 diabetes ,Government ,business.industry ,education ,Stigma (botany) ,medicine.disease ,Narrative inquiry ,Integrated care ,Nursing ,Health care ,medicine ,Narrative ,business ,Psychology ,General Nursing ,Qualitative research - Abstract
Objective: To explore the experiences of Australian parents caring for a child using intensive insulin therapy in the early primary school setting to identify facilitators of this therapy and implications for parents. Background: Young children with type 1 diabetes require adult support when administering insulin in the early primary school setting, yet availability of school support, such as from nurses, is inconsistent across Australia. This increases the burden on parents and in some circumstances, insulin is avoided at school. Study design and methods: This study was a qualitative research design using narrative inquiry. Mothers (n=14) from six Australian states/territories with children attending Government, Catholic and Independent schools participated in semi-structured telephone interviews between December 2014 and September 2016. Narrative analysis was used to interpret the interview data. Results: Nine narrative threads told the collective story of mothers’ experiences supporting their child with intensive insulin therapy at school. Facilitators of intensive insulin therapy were collaborative partnerships between parents and school staff, diabetes education for school staff, reasonable adjustments for integrated care and the use of continuous glucose monitoring systems. Implications for mothers were the stigma of advocating, being worried about their child’s safety in other people’s care, restricted employment, wanting their child to be like everyone else, and providing 24/7 care behind the scenes. Despite these challenges, all children received intensive insulin therapy at school. Discussion and conclusion: The findings of this study indicate that the Australian education system lacks appropriate health support structures required for children with type 1 diabetes. In order to facilitate diabetes care at school non-nursing staff are trained to administer or supervise insulin and the overall responsibility is transferred onto parents. Implications for policy and nursing practice: Nurses working as diabetes educators need to be aware of the burden on parents and advocate for more supportive practices to facilitative intensive insulin therapy in the early primary school setting. Parents, in collaboration with health and education departments, should demand the allocation of appropriately qualified school nurses to legally provide high quality diabetes care that children are entitled to. If current practices, dictated by insufficient resources continue, the Australian Government will make the assumption that existing systems are adequately meeting the needs of students with type 1 diabetes. What is already known about the topic? Children with chronic health conditions have a high risk of poor educational outcomes. Most Australian schools do not employ nurses. Teaching and administration staff are frequently used for healthcare support including the management of diabetes. What this paper adds: This study is the first to provide qualitative insight into the experience of Australian mothers supporting their child with type 1 diabetes using intensive insulin therapy in the early primary school setting. The findings highlight the significant physical, emotional and financial impact on mothers who support intensive insulin therapy. This paper provides an awareness of the disconnect between mandatory school attendance, accessing education on the same basis as others according to the Disability Standards for Education, and the availability of school nurses to legally administer insulin.
- Published
- 2021
46. B cells, antibody-secreting cells, and virus-specific antibodies respond to herpes simplex virus 2 reactivation in skin
- Author
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Tao Peng, Paul T. Edlefsen, Anna Wald, Danica Shao, RuthMabel Boytz, Savanna S Carmack, Christine Johnston, Anton M Sholukh, Raabya Rossenkhan, Alexis Klock, Lawrence Corey, Jia Zhu, Khamsone Phasouk, and Emily S Ford
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Herpesvirus 2, Human ,Antibodies, Viral ,medicine.disease_cause ,Immunoglobulin D ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,medicine ,Humans ,Skin ,CD20 ,B-Lymphocytes ,Herpes Genitalis ,biology ,medicine.diagnostic_test ,Herpes Simplex ,General Medicine ,Acquired immune system ,Molecular biology ,030104 developmental biology ,Herpes simplex virus ,Immunoglobulin G ,030220 oncology & carcinogenesis ,Skin biopsy ,Commentary ,biology.protein ,Female ,Virus Activation ,Antibody ,Research Article - Abstract
Tissue-based T cells are important effectors in the prevention and control of mucosal viral infections; less is known about tissue-based B cells. We demonstrate that B cells and antibody-secreting cells (ASCs) are present in inflammatory infiltrates in skin biopsy specimens from study participants during symptomatic herpes simplex virus 2 (HSV-2) reactivation and early healing. Both CD20(+) B cells, most of which are antigen inexperienced based on their coexpression of IgD, and ASCs — characterized by dense IgG RNA expression in combination with CD138, IRF4, and Blimp-1 RNA — were found to colocalize with T cells. ASCs clustered with CD4(+) T cells, suggesting the potential for crosstalk. HSV-2–specific antibodies to virus surface antigens were also present in tissue and increased in concentration during HSV-2 reactivation and healing, unlike in serum, where concentrations remained static over time. B cells, ASCs, and HSV-specific antibody were rarely detected in biopsies of unaffected skin. Evaluation of samples from serial biopsies demonstrated that B cells and ASCs followed a more migratory than resident pattern of infiltration in HSV-affected genital skin, in contrast to T cells. Together, these observations suggest the presence of distinct phenotypes of B cells in HSV-affected tissue; dissecting their role in reactivation may reveal new therapeutic avenues to control these infections.
- Published
- 2021
47. Cytomegalovirus shedding from breastmilk and mucosal sites in healthy postpartum women: A pilot study
- Author
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Anna Wald, Benjamin Zaniello, Tali Azenkot, Christine Johnston, Amalia Magaret, Margaret L. Green, Stacy Selke, and Meei-Li Huang
- Subjects
Saliva ,business.industry ,Transmission (medicine) ,Congenital cytomegalovirus infection ,virus diseases ,Physiology ,medicine.disease ,Virology ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,medicine.anatomical_structure ,Vagina ,Medicine ,030211 gastroenterology & hepatology ,Sex organ ,030212 general & internal medicine ,Young adult ,Viral shedding ,business ,Postpartum period - Abstract
Mother-to-child cytomegalovirus (CMV) breastmilk transmission can occur in the postnatal period. In a pilot study, we measured daily CMV detection by polymerase chain reaction in breastmilk, vaginal, and saliva samples from nine healthy CMV-seropositive postpartum women for 28 days. CMV was found in seven of nine women and 171 of 253 breastmilk samples (67.6%). In four women, all breastmilk samples were positive. CMV was less frequently detected in the vagina (39 of 258, 15.1%) and saliva (53 of 258, 20.5%). Daily breastmilk, oral, and genital collection is feasible and demonstrates high variability between women. Further study of the dynamics of CMV in distinct anatomic compartments is warranted.
- Published
- 2019
48. Uptake of treatment practice standards during a pandemic in an academic medical system
- Author
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Jeannie D. Chan, Christine Johnston, Shireesha Dhanireddy, Rupali Jain, Maria Tate, and Margaret L. Green
- Subjects
Microbiology (medical) ,Medical education ,Academic Medical Centers ,Epidemiology ,business.industry ,COVID-19 ,Infectious Diseases ,Pandemic ,Treatment practice ,Medicine ,Humans ,business ,Pandemics ,Letter to the Editor - Published
- 2021
49. Distinct populations of antigen-specific tissue-resident CD8+ T cells in human cervix mucosa
- Author
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David M. Koelle, Julie Czartoski, Annalyssa N Long, Lei Jin, Noel A Williams, Khamsone Phasouk, Harlan Robins, Emily L Bossard, Christine Johnston, Alexis Klock, Tao Peng, Thomas M. Snyder, Jia Zhu, Kerry J. Laing, Jason H. Bielas, Dana Varon, M. Juliana McElrath, Anna Wald, and Lawrence Corey
- Subjects
Antigens, Differentiation, T-Lymphocyte ,CD4-Positive T-Lymphocytes ,Ectocervix ,Herpesvirus 2, Human ,Immunology ,Adaptive immunity ,T cells ,Cervix Uteri ,Biology ,CD8-Positive T-Lymphocytes ,Immunophenotyping ,Memory T Cells ,Antigens, CD ,Virology ,medicine ,Cytotoxic T cell ,Humans ,Lectins, C-Type ,Mucous Membrane ,T-cell receptor ,General Medicine ,Acquired immune system ,Phenotype ,Epithelium ,Genes, T-Cell Receptor ,medicine.anatomical_structure ,Female ,Immunologic Memory ,Integrin alpha Chains ,CD8 ,Ex vivo ,Research Article - Abstract
The ectocervix is part of the lower female reproductive tract (FRT), which is susceptible to sexually transmitted infections (STIs). Comprehensive knowledge of the phenotypes and T cell receptor (TCR) repertoire of tissue-resident memory T cells (TRMs) in the human FRT is lacking. We took single-cell RNA-Seq approaches to simultaneously define gene expression and TCR clonotypes of the human ectocervix. There were significantly more CD8+ than CD4+ T cells. Unsupervised clustering and trajectory analysis identified distinct populations of CD8+ T cells with IFNGhiGZMBloCD69hiCD103lo or IFNGloGZMBhiCD69medCD103hi phenotypes. Little overlap was seen between their TCR repertoires. Immunofluorescence staining showed that CD103+CD8+ TRMs were preferentially localized in the epithelium, whereas CD69+CD8+ TRMs were distributed evenly in the epithelium and stroma. Ex vivo assays indicated that up to 14% of cervical CD8+ TRM clonotypes were HSV-2 reactive in HSV-2-seropositive persons, reflecting physiologically relevant localization. Our studies identified subgroups of CD8+ TRMs in the human ectocervix that exhibited distinct expression of antiviral defense and tissue residency markers, anatomic locations, and TCR repertoires that target anatomically relevant viral antigens. Optimization of the location, number, and function of FRT TRMs is an important approach for improving host defenses to STIs.
- Published
- 2021
50. Impact of the menstrual cycle and ethinyl estradiol/etonogestrel contraceptive vaginal ring on granulysin and other mucosal immune mediators
- Author
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Florian Hladik, Jeanne M. Marrazzo, Elizabeth Micks, Urvashi Pandey, Christine Johnston, and Sean M. Hughes
- Subjects
0301 basic medicine ,Adult ,Antigens, Differentiation, T-Lymphocyte ,endocrine system ,media_common.quotation_subject ,Immunology ,Physiology ,Luteal phase ,Endometrium ,Ethinyl Estradiol ,Article ,03 medical and health sciences ,0302 clinical medicine ,Follicular phase ,Contraceptive Agents, Female ,Immunology and Allergy ,Medicine ,Humans ,Etonogestrel ,Immunity, Mucosal ,reproductive and urinary physiology ,Menstrual cycle ,Menstrual Cycle ,media_common ,030219 obstetrics & reproductive medicine ,Desogestrel ,urogenital system ,business.industry ,Obstetrics and Gynecology ,Contraceptive Devices, Female ,Middle Aged ,Vaginal ring ,030104 developmental biology ,medicine.anatomical_structure ,Reproductive Medicine ,Vagina ,Female ,business ,Fallopian tube ,medicine.drug - Abstract
PROBLEM: Changes in sex hormones during the menstrual cycle and contraceptive vaginal ring (CVR) use influence immunity within the female genital tract, but the magnitude of these effects and their anatomical location are unclear. METHOD OF STUDY: In a prospective study, 29 women were assessed at three-time points: follicular phase, luteal phase, and one month after initiation of the ethinyl estradiol/etonogestrel CVR (NuvaRing®, Merck). We performed microarrays on endocervical cytobrushes and measured immune mediators in cervicovaginal fluid, adjusting for bacterial vaginosis and the presence of blood. We compared these results to public gene expression data from the fallopian tubes, endometrium, endo- and ectocervix, and vagina. RESULTS: Immune-related gene expression in the endocervix and immune mediators in cervicovaginal fluid increased during CVR use versus both menstrual phases, and in the follicular versus luteal phase. The antimicrobial protein granulysin was high during CVR use, intermediate in the follicular phase, and nearly absent from the luteal phase. Re-analysis of public gene expression data confirmed increased immune-related gene expression in the endocervix during the follicular phase. However, in the fallopian tube, endometrium, and vagina, the follicular phase showed immunosuppression. CONCLUSIONS: Immune-related genes in the cervicovaginal tract were highest during CVR use, intermediate in the follicular phase, and lowest in the luteal phase. Granulysin is a potential biomarker of menstrual phase: Frequently detected in follicular samples, but rare in luteal. Lastly, immunological differences between the follicular and luteal phases vary throughout the female genital tract.
- Published
- 2021
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