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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.).

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.

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)

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.

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

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.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. We assess the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. All prime-boost combinations substantially increase the neutralization titers to Omicron, although the boosted titers decline rapidly within 2 months from the peak response compared with boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers are substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared with homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generates nearly equivalent neutralizing activity against Omicron sublineages BA.1, BA.2, and BA.3 but modestly reduced neutralizing activity against BA.2.12.1 and BA.4/BA.5 compared with BA.1. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2. This trial was conducted under ClincalTrials.gov: NCT04889209.

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.

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.

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.

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.

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.

Background Prevention interventions for coronavirus disease (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), are currently limited to non-pharmaceutical strategies. Observational and laboratory data suggested that hydroxychloroquine (HCQ) had biologic activity against SARS-CoV-2. A blinded trial of HCQ in persons with confirmed exposure and virologic and clinical endpoints is needed. Methods We conducted a national, householdrandomized, double-blind, controlled trial of HCQ post-exposure prophylaxis, with entirely remote study procedures. We enrolled close contacts exposed to persons with SARS-CoV-2 infection in the past 96 hours. Participants were randomized to either HCQ (400 mg daily for three days followed by 200 mg daily for eleven days) or ascorbic acid (500 mg followed by 250 mg daily), as a placebo-equivalent control. Participants self-collected mid-turbinate swabs daily (days 1–14) for SARS-CoV-2 PCR testing. The primary outcome was PCR-confirmed, incident SARS-CoV-2 infection among persons SARS-CoV-2 negative at enrollment. Symptoms were assessed using criteria from the US CDC. Results From March-August 2020, 623 households were randomized; 311 households (381 participants) to the HCQ group and 312 households (400 participants) to the control group. Ninety- one percent of participants were retained up to day 14 and 9,595 of 10,588 (91%) of swabs were tested. Among participants who were SARS-CoV-2 negative at baseline (n=626/781, 80%), the cumulative incidence of SARS-CoV-2 was 14.5% (95% CI: 11.6–17.4) and the cumulative incidence of COVID-19 symptoms was 11.6% (95% CI: 8.9–14.2) at day 14. By day 14, there was no difference between the HCQ group and control group in SARS-CoV-2 acquisition (46 vs. 43 events, aHR= 0.99, 95% CI 0.64–1.52, p=0.95) or symptomatic disease (40 vs. 32 events, aHR= 1.23, 95% CI: 0.76–1.99, p=0.40). The adverse event frequency was similar between groups (59 [15.5%] participants in the HCQ and 45 [11.3%] in the control group, p=0.092). Cumulative incidence of RT-PCR-confirmed SARS-CoV-2 infection among close contacts of diagnosed cases, by study group Conclusion This randomized, double-blind, controlled trial among persons with recent exposure and high incidence of SAR-CoV2 provides strong evidence that HCQ post-exposure prophylaxis did not prevent SARS-CoV-2 infection or modify clinical disease. Disclosures Anna Bershteyn, PhD, Bill and Melinda Gates Foundation (Grant/Research Support)Gates Ventures (Consultant)National Institutes of Health (Grant/Research Support) Kristopher M. Paolino, MD, MTM&H, Nothing to disclose Raphael J. Landovitz, MD, MSc, Gilead (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Other Financial or Material Support, Speaker Honoraria) Anna Wald, MD, MPH, Aicuris (Individual(s) Involved: Self): Consultant; Gilead (Individual(s) Involved: Self): Consultant; GlaxoSmithKline (Individual(s) Involved: Self): Scientific Research Study Investigator; Merck (Individual(s) Involved: Self): DSMB participation; provision of vaccine for a study, Other Financial or Material Support; Sanofi (Individual(s) Involved: Self): Scientific Research Study Investigator; X-Vax (Individual(s) Involved: Self): Consultant Helen Y. Chu, MD MPH, Cepheid (Grant/Research Support)Ellume (Grant/Research Support)Glaxo Smith Kline (Consultant)Merck (Consultant)Sanofi-Pasteur (Grant/Research Support)

Antigen (Ag)-specific immune responses to chronic infections, such as herpes simplex virus type 2 (HSV-2) in HIV/HSV-coinfected persons, may sustain HIV tissue reservoirs by promoting T-cell proliferation but are poorly studied in women on antiretroviral therapy (ART). Mixed anogenital swabs and cervical secretions were self-collected by nine HIV/HSV-2-coinfected women during ART for 28 days to establish subclinical HSV DNA shedding rates and detection of HIV RNA by real-time PCR. Typical herpes lesion site biopsy (TLSB) and cervical biopsy specimens were collected at the end of the daily sampling period. Nucleic acids (NA) isolated from biopsy specimens had HIV quantified and HIV envC2-V5 single-genome amplification (SGA) and T-cell receptor (TCR) repertoires assessed. Women had a median CD4 count of 537 cells/μl (IQR: 483 to 741) at enrollment and HIV plasma viral loads of

Clinical trials have ruled out a role of hydroxychloroquine in the treatment of COVID-19, but it has been hypothesized that hydroxychloroquine's activity against SARS-CoV-2 in the laboratory suggests a role in prevention. This randomized controlled trial tests hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection., Visual Abstract. Postexposure Hydroxychloroquine Prophylaxis to Prevent SARS-CoV-2 Infection Clinical trials have ruled out a role of hydroxychloroquine in the treatment of COVID-19, but it has been hypothesized that hydroxychloroquine's activity against SARS-CoV-2 in the laboratory suggests a role in prevention. This randomized controlled trial tests hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection. Visual Abstract. Postexposure Hydroxychloroquine Prophylaxis to Prevent SARS-CoV-2 Infection Clinical trials have ruled out a role of hydroxychloroquine in the treatment of COVID-19, but it has been hypothesized that hydroxychloroquine's activity against SARS-CoV-2 in the laboratory suggests a role in prevention. This randomized controlled trial tests hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection., Background: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention. Objective: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection. Design: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961) Setting: National U.S. multicenter study. Participants: Close contacts recently exposed ( 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026). Limitation: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days. Conclusion: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection. Primary Funding Source: Bill & Melinda Gates Foundation.

Coronavirus disease 2019 (COVID‐19) due to infection with severe acute respiratory syndrome coronavirus 2 causes substantial morbidity. Tocilizumab, an interleukin‐6 receptor antagonist, might improve outcomes by mitigating inflammation. We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID‐19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two‐point reduction in severity on a six‐point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional‐hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab. We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced C‐reactive protein, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% confidence interval [CI], 0.38–2.22) or mortality (aHR, 0.57; 95% CI, 0.21–1.52). A numerically higher proportion of tocilizumab‐treated patients had subsequent infections, transaminitis, and cytopenias. Tocilizumab did not improve outcomes in hospitalized patients with COVID‐19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.