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Background: Previous research has shown that vaccination reduces risk of post-coronavirus disease 2019 (COVID-19) venous thrombosis or embolism (VTE), but the effect of vaccine boosting on post-COVID-19 VTE risk reduction is unclear. We sought to estimate the effect of COVID-19 vaccination on the risk of post-COVID-19 VTE and to examine if the magnitude of this association differed among variant eras., Methods: We performed a case-control study of Military Health System (MHS) beneficiaries who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020-2022. Cases were defined as those with medically attended VTE within 90 days after their first positive SARS-CoV-2 test; controls were defined as SARS-CoV-2 infections without incident VTE by 90 days. Multivariate logistic regression estimated the odds of post-SARS-CoV-2 VTE based on pre-COVID-19 vaccine status, adjusting for other VTE risk factors., Results: A total of 4646 MHS beneficiaries were included in this analysis; 1370 received a primary vaccine series and a further 790 received at least 1 booster at time of infection; 71 had VTE within 90 days of SARS-CoV-2 infection. Those who were vaccinated had lower odds of VTE (adjusted odds ratio [95% confidence interval]) compared to the unvaccinated following infection (primary series: 0.28 [.13-.62]; booster dose: 0.06 [.01-.46]). Post-COVID-19 VTE risk was lowest during the Omicron era, but VTEs were too rare to examine for an interaction of variant era and vaccine effect., Conclusions: Among MHS beneficiaries, COVID-19 vaccination was associated with a reduced risk of post-COVID-19 VTE diagnosis; estimated risk reduction was larger among those who received a booster., Competing Interests: Potential conflicts of interest. S. D. P., T. H. B., D. R. T., and M. P. S. report that the Uniformed Services University (USU) IDCRP, a US DOD institution, and HJF were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase 3 COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the DOD Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase 3 vaccine trial sponsored by AstraZeneca. Both trials were part of the US government COVID-19 response. Neither is related to the work presented here. R. C. M. receives research support paid to his institution from Sound Pharmaceuticals for an investigational COVID-19 therapeutic and from GeoVax for an investigational COVID-19 vaccine candidate, both unrelated to the work presented here. All other authors report no potential conflicts of interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Coronavirus disease 2019 (COVID-19) vaccine breakthrough infections have been important for all circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant periods, but the contribution of vaccine-specific SARS-CoV-2 viral diversification to vaccine failure remains unclear. This study analyzed 595 SARS-CoV-2 sequences collected from the Military Health System beneficiaries between December 2020 and April 2022 to investigate the impact of vaccination on viral diversity. By comparing sequences based on the vaccination status of the participant, we found limited evidence indicating that vaccination was associated with increased viral diversity in the SARS-CoV-2 spike, and we show little to no evidence of a substantial sieve effect within major variants; rather, we show that rapid variant replacement constrained intragenotype COVID-19 vaccine strain immune escape. These data suggest that, during past and perhaps future periods of rapid SARS-CoV-2 variant replacement, vaccine-mediated effects were subsumed with other drivers of viral diversity due to the massive scale of infections and vaccinations that occurred in a short time frame. However, our results also highlight some limitations of using sieve analysis methods outside of placebo-controlled clinical trials., Competing Interests: The views expressed are those of the authors and do not reflect the official policy of the Uniformed Services University of the Health Sciences (USUHS), Department of the Army, Department of the Navy, the Department of the Air Force, the Department of Defense or the US Government, and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). The investigators have adhered to the policies for protection of human subjects as prescribed in 45 CFR 46. Drs Berjohn, Fries, Smith, Mody, Huprikar, Lindholm, Jones, Larson, Ewers; Ms Bazan; and Drs Saunders, Maldonado, Simons, Tribble, and Burgess are service members or employees of the US Government. This work was prepared as part of their official duties. Title 17 USC §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 USC §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints., Methods: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms., Results: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms., Conclusions: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Chronic neuropsychological sequelae following SARS-CoV-2 infection, including depression, anxiety, fatigue, and general cognitive difficulties, are a major public health concern. Given the potential impact of long-term neuropsychological impairment, it is important to characterize the frequency and predictors of this post-infection phenotype., Methods: The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal study assessing the impact of SARS-CoV-2 infection in U.S. Military Healthcare System (MHS) beneficiaries, i.e. those eligible for care in the MHS including active duty servicemembers, dependents, and retirees. Four broad areas of neuropsychological symptoms were assessed cross-sectionally among subjects 1-6 months post-infection/enrollment, including: depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), fatigue (PROMIS® Fatigue 7a), and cognitive function (PROMIS® Cognitive Function 8a and PROMIS® Cognitive Function abilities 8a). Multivariable Poisson regression models compared participants with and without SARS-CoV-2 infection history on these measures, adjusting for sex, ethnicity, active-duty status, age, and months post-first positive or enrollment of questionnaire completion (MPFP/E); models for fatigue and cognitive function were also adjusted for depression and anxiety scores., Results: The study population included 2383 participants who completed all five instruments within six MPFP/E, of whom 687 (28.8%) had at least one positive SARS-CoV-2 test. Compared to those who had never tested positive for SARS-CoV-2, the positive group was more likely to meet instrument-based criteria for depression (15.4% vs 10.3%, p<0.001), fatigue (20.1% vs 8.0%, p<0.001), impaired cognitive function (15.7% vs 8.6%, p<0.001), and impaired cognitive function abilities (24.3% vs 16.3%, p<0.001). In multivariable models, SARS-CoV-2 positive participants, assessed at an average of 2.7 months after infection, had increased risk of moderate to severe depression (RR: 1.44, 95% CI 1.12-1.84), fatigue (RR: 2.07, 95% CI 1.62-2.65), impaired cognitive function (RR: 1.64, 95% CI 1.27-2.11), and impaired cognitive function abilities (RR: 1.41, 95% CI 1.15-1.71); MPFP/E was not significant., Conclusions: Participants with a history of SARS-CoV-2 infection were up to twice as likely to report cognitive impairment and fatigue as the group without prior SARS-CoV-2 infection. These findings underscore the continued importance of preventing SARS-CoV-2 infection and while time since infection/enrollment was not significant through 6 months of follow-up, this highlights the need for additional research into the long-term impacts of COVID-19 to mitigate and reverse these neuropsychological outcomes., Competing Interests: Potential conflicts of interest. S. D. P., T. H. B., J.S.R., and M.P.S. report that the Uniformed Services University (USU) Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and the Henry M. Jackson Foundation (HJF) were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US Government COVID-19 response. Neither is related to the work presented here. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The consequences of low-level viremia in people with HIV are unclear. We used data from the US Military HIV Natural History Study to examine the association of low-level viremia (LLV) and serious non-AIDS events (SNAEs)., Methods: Included participants initiated antiretroviral therapy after 1996 and had ≥3 viral loads (VLs) measured, using an assay with a lower limit of detection of <50 copies/mL, ≥6 months after antiretroviral therapy initiation. VLs were categorized as lower levels of LLV (51-199 copies/mL), higher level of low-level viremia (HLLV; 200-999 copies/mL), and (VF; ≥200 copies/mL on 2 or more successive determinations or a single VL ≥1000 copies/mL), and virologic suppression (VS; ie, VL <50 copies/mL). Viral blips (ie, VLs between 50 and 999 copies/mL that are preceded and succeeded by VL <50 copies/mL) were analyzed in the VS category. Cox proportional hazards models were used to examine the association of LLV and SNAEs, adjusted hazard ratios and 95% confidence intervals are presented., Results: A total of 439 (17.4%) SNAEs were recorded among the 2528 participants (93% male, 40% Caucasian, 43% African American) followed for a median of 11 years. In 8.5% and 4.6% of the participants, respectively, LLV and HLLV were the highest recorded viremia strata. Compared with VS, SNAEs were associated with LLV (1.3 [1.2-1.4]), HLLV (1.6 [1.5-1.7]), and virologic failure (1.7 [1.7-1.8])., Conclusions: The results of this study suggest that LLV is associated with the occurrence of SNAEs and needs further study., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Importance: The travelers' gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers' diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers' microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD-even in moderate to severe cases or in regions with high infectious disease burden-is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care., Competing Interests: The authors declare no conflict of interest.

Subtype B HIV-1 has been the primary driver of the HIV-1 epidemic in the United States (U.S.) for over forty years and is also a prominent subtype in the Americas, Europe, Australia, the Middle East and North Africa. In this study, the neutralization profiles of contemporary subtype B Envs from the U.S. were assessed to characterize changes in neutralization sensitivities over time. We generated a panel of 30 contemporary pseudoviruses (PSVs) and demonstrated continued diversification of subtype B Env from the 1980s up to 2018. Neutralization sensitivities of the contemporary subtype B PSVs were characterized using 31 neutralizing antibodies (NAbs) and were compared with strains from earlier in the HIV-1 pandemic. A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 NAbs for the contemporary as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the NAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A meta-analysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The long-term effects of coronavirus disease 2019 (COVID-19) on physical fitness are unclear, and the impact of vaccination on that relationship is uncertain., Methods: We compared survey responses in a 1-year study of US military service members with (n = 1923) and without (n = 1591) a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We fit Poisson regression models to estimate the association between history of SARS-CoV-2 infection and fitness impairment, adjusting for time since infection, demographics, and baseline health., Results: The participants in this analysis were primarily young adults aged 18-39 years (75%), and 71.5% were male. Participants with a history of SARS-CoV-2 infection were more likely to report difficulty exercising (38.7% vs 18.4%; P < .01), difficulty performing daily activities (30.4% vs 12.7%; P < .01), and decreased fitness test (FT) scores (42.7% vs 26.2%; P < .01) than those without a history of infection. SARS-CoV-2-infected participants were at higher risk of these outcomes after adjusting for other factors (unvaccinated: exercising: adjusted risk ratio [aRR], 3.99; 95% CI, 3.36-4.73; activities: aRR, 5.02; 95% CI, 4.09-6.16; FT affected: aRR, 2.55; 95% CI, 2.19-2.98). Among SARS-CoV-2-positive participants, full vaccination before infection was associated with a lower risk of post-COVID-19 fitness impairment (fully vaccinated: exercise: aRR, 0.81; 95% CI, 0.70-0.95; activities: aRR, 0.76; 95% CI, 0.64-0.91; FT: aRR, 0.87; 95% CI, 0.76-1.00; boosted: exercise: aRR, 0.62; 95% CI, 0.51-0.74; activities: aRR, 0.52; 95% CI, 0.41-0.65; FT: aRR, 0.59; 95% CI, 0.49-0.70)., Conclusions: In this study of generally young, healthy military service members, SARS-CoV-2 infection was associated with lower self-reported fitness and exercise capacity; vaccination and boosting were associated with lower risk of self-reported fitness loss., Competing Interests: Potential conflicts of interest. 1045 S.D.P., T.H.B., J.S.R., and M.P.S. report that the Uniformed Services University (USU) Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and the HJF were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both trials were part of the US Government COVID-19 response. Neither is related to the work presented here. R.C.M. receives research support paid to his institution from Sound Pharmaceuticals for an investigational COVID-19 therapeutic unrelated to the work presented here. M.J.M. is a paid speaker for Xarelto (Janssen Pharmaceuticals). All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: We evaluated the impact of infectious disease (ID) syndromes on US active duty (AD) servicemembers returning from overseas deployment (DEP), military training exercises (EXR), or short-term military travel (eg, temporary assignment of duty [TDY])., Methods: We conducted a survey-based assessment of US AD servicemembers returning from DEP, EXR, or TDY between 2015 and 2019. Subjects completed a post-travel survey capturing symptoms of travelers' diarrhea (TD), influenza-like illness (ILI), and febrile illness (FI). Risk factors associated with any ID syndrome (ie, either TD, ILI, or FI) that impacted daily activities were assessed using a logistic regression model with backward selection., Results: One-third of servicemembers (654/1822) experienced an ID syndrome, and 26% (471/1822) reported a ≥50% reduction in activity level due to an ID syndrome (median duration, 3 days). TD was the most common ID syndrome experienced and accounted for 73% (346/471) of ID syndromes impacting daily activities. The greatest impact of ID syndromes was observed in servicemembers on DEP. Compared with servicemembers on EXR or TDY, those on DEP had a longer duration of travel and a delayed period of risk for ID syndromes. Multivariate analysis identified high-risk exposures (ie, environmental exposures, close contact with locals, consuming food from street vendors) and behaviors (ie, inability to sanitize hands before meals) that could be used to inform mitigation strategies., Conclusions: ID syndromes result in a significant loss of productivity during military travel. Addressing modifiable risk factors and access to TD self-treatment in high-risk settings may help mitigate the impact of ID threats during military travel., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

The rapid emergence of SARS-CoV-2 variants challenges vaccination strategies. Here, we collected 201 serum samples from persons with a single infection or multiple vaccine exposures, or both. We measured their neutralization titers against 15 natural variants and 7 variants with engineered spike mutations and analyzed antigenic diversity. Antigenic maps of primary infection sera showed that Omicron sublineages BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and more similar to Beta/Gamma/Mu variants. Three mRNA COVID-19 vaccinations increased neutralization of BA.1 more than BA.4/BA.5 or BA.2.12.1. BA.1 post-vaccination infection elicited higher neutralization titers to all variants than three vaccinations alone, although with less neutralization to BA.2.12.1 and BA.4/BA.5. Those with BA.1 infection after two or three vaccinations had similar neutralization titer magnitude and antigenic recognition. Accounting for antigenic differences among variants when interpreting neutralization titers can aid the understanding of complex patterns in humoral immunity that informs the selection of future COVID-19 vaccine strains., Competing Interests: Declaration of interests S.D.P., T.H.B, D.R.T., J.S.R., and M.P.S. report that the Uniformed Services University (USU) Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and the Henry M. Jackson Foundation (HJF) were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both trials were part of the U.S. Government COVID-19 response. Neither is related to the work presented here., (Published by Elsevier Inc.)

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear., Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial)., Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4])., Setting: 94 hospitals in 10 countries (86% U.S. participants)., Participants: Adults hospitalized with COVID-19., Intervention: SOC., Measurements: 28-day mortality and recovery., Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages., Limitation: Unmeasured confounding., Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas., Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Objective: To describe the clinical characteristics and outcome of Abiotrophia and Granulicatella infective endocarditis and compare them with Viridans group streptococci infective endocarditis., Methods: All patients in the International Collaboration on Endocarditis (ICE) - prospective cohort study (PCS) and the ICE-PLUS cohort were included (n = 8112). Data from patients with definitive or possible IE due to Abiotrophia species, Granulicatella species and Viridans group streptococci was analyzed. A propensity score (PS) analysis comparing the ABI/GRA-IE and VGS-IE groups according to a 1:2 ratio was performed., Results: Forty-eight (0.64%) cases of ABI/GRA-IE and 1,292 (17.2%) VGS-IE were included in the analysis. The median age of patients with ABI/GRA-IE was lower than VGS-IE (48.1 years vs. 57.9 years; p = 0.001). Clinical features and the rate of in-hospital surgery was similar between ABI/GRA-IE and VGS-IE (52.1% vs. 45.4%; p = 0.366). Unadjusted in-hospital death was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 8.8%; p = 0.003), and cumulative six-month mortality was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 11.9%; p<0.001). After PS analysis, in-hospital mortality was similar in both groups, but six-month mortality was lower in the ABI/GRA IE group (2.1% vs. 10.4%; p = 0.029)., Conclusions: Patients with ABI/GRA-IE were younger, had similar clinical features and rates of surgery and better prognosis than VGS-IE., (Copyright © 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

The rapid spread of the highly contagious Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) along with its high number of mutations in the spike gene has raised alarms about the effectiveness of current medical countermeasures. To address this concern, we measured the neutralization of the Omicron BA.1 variant pseudovirus by postvaccination serum samples after two and three immunizations with the Pfizer/BioNTech162b2 SARS-CoV-2 mRNA (Pfizer/BNT162b2) vaccine, convalescent serum samples from unvaccinated individuals infected by different variants, and clinical-stage therapeutic antibodies. We found that titers against the Omicron variant were low or undetectable after two immunizations and in many convalescent serum samples, regardless of the infecting variant. A booster vaccination increased titers more than 30-fold against Omicron to values comparable to those seen against the D614G variant after two immunizations. Neither age nor sex was associated with the differences in postvaccination antibody responses. We also evaluated 18 clinical-stage therapeutic antibody products and an antibody mimetic protein product obtained directly from the manufacturers. Five monoclonal antibodies, the antibody mimetic protein, three antibody cocktails, and two polyclonal antibody preparations retained measurable neutralization activity against Omicron with a varying degree of potency. Of these, only three retained potencies comparable to the D614G variant. Two therapeutic antibody cocktails in the tested panel that are authorized for emergency use in the United States did not neutralize Omicron. These findings underscore the potential benefit of mRNA vaccine boosters for protection against Omicron and the need for rapid development of antibody therapeutics that maintain potency against emerging variants.

The rapid spread of the highly contagious Omicron variant of SARS-CoV-2 along with its high number of mutations in the spike gene has raised alarm about the effectiveness of current medical countermeasures. To address this concern, we measured neutralizing antibodies against Omicron in three important settings: (1) post-vaccination sera after two and three immunizations with the Pfizer/BNT162b2 vaccine, (2) convalescent sera from unvaccinated individuals infected by different variants, and (3) clinical-stage therapeutic antibodies. Using a pseudovirus neutralization assay, we found that titers against Omicron were low or undetectable after two immunizations and in most convalescent sera. A booster vaccination significantly increased titers against Omicron to levels comparable to those seen against the ancestral (D614G) variant after two immunizations. Neither age nor sex were associated with differences in post-vaccination antibody responses. Only three of 24 therapeutic antibodies tested retained their full potency against Omicron and high-level resistance was seen against fifteen. These findings underscore the potential benefit of booster mRNA vaccines for protection against Omicron and the need for additional therapeutic antibodies that are more robust to highly mutated variants., One Sentence Summary: Third dose of Pfizer/BioNTech COVID-19 vaccine significantly boosts neutralizing antibodies to the Omicron variant compared to a second dose, while neutralization of Omicron by convalescent sera, two-dose vaccine-elicited sera, or therapeutic antibodies is variable and often low.

The impact of HIV on influenza-like illness (ILI) has been incompletely described in the era of combination antiretroviral therapy, particularly in the post-H1N1 pandemic period. This analysis informs on ILI in an otherwise healthy, predominantly outpatient cohort of adults with HIV in the USA. From September 2010 to March 2015, this multisite observational cohort study enrolled otherwise healthy adults presenting to a participating US military medical center with ILI, a subset of whom were HIV positive. Demographics, clinical data, and self-reported symptom severity were ascertained, and enrollees completed a daily symptom diary for up to 10 days. 510 men were included in the analysis; 50 (9.8%) were HIV positive. Subjects with HIV were older and less likely to be on active duty. Rhinovirus and influenza A were the most commonly identified pathogens. Moderate-severe diarrhea (p<0.001) and fatigue (p=0.01) were more frequently reported by HIV-positive men. HIV positivity was associated with higher gastrointestinal scores, but not other measures of ILI symptom severity, after controlling for age, race, military status, and influenza season. Few were hospitalized. HIV-positive subjects had more influenza B (p=0.04) and were more likely to receive antivirals (32% vs 6%, p<0.01). Antiviral use was not significantly associated with symptom scores when accounting for potential confounders. In this predominantly outpatient cohort of adult men, HIV had minimal impact on ILI symptom severity. Despite similar illness severity, a higher percentage of subjects with HIV reported undergoing antiviral treatment for ILI, likely reflecting differences in prescribing practices.Trial registration number: NCT01021098., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Coronavirus disease 2019 (COVID-19) presents a unique challenge to United States Navy hospital ships. The aim of this study was to determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among US Navy personnel deployed on the USNS COMFORT to augment the inpatient health care capacity in New York City., Methods: This was a cross-sectional study conducted on USNS COMFORT crewmembers returning to Norfolk, Virginia, following deployment. Participants completed an electronic questionnaire and provided a serum sample at Day 14 post-deployment. Polymerase chain reaction (PCR) results from testing of symptomatic crewmembers during deployment and Day 0 and Day 14 post-deployment screening swabs conducted on all crewmembers, per military order, were abstracted. SARS-CoV-2 infection was defined as a positive SARS-CoV-2 spike glycoprotein immunoglobulin G antibody or PCR result., Results: Of the ship's total complement of 1200 crewmembers, 450 were enrolled: 432 (96.0%) completed the questionnaire and provided a serum sample. The median age of participants (interquartile range) was 30 (24-39) years, 50.8% were female, 58.6% were White, and 14.0% were Black; 80.1% had a clinical role during deployment. The cumulative prevalence of SARS-CoV-2 infection was 3.01% (13/432; 95% CI, 1.61%-5.09%). Twelve of 13 infections occurred in health care providers, and 8 of 13 were asymptomatic. The antibody profile of infected crewmembers varied by suspected timing of infection., Conclusions: We observed a low prevalence of SARS-CoV-2 infection among USNS COMFORT crewmembers despite the inherent risk of a shipboard deployment to an area with high rates of community transmission. Our findings suggest that early infection control measures mitigated the spread of SARS-CoV-2 among crewmembers., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Risk behaviors associated with sexually transmitted infections (STIs) among people living with HIV (PLWH) have not been well characterized in the US military. We identified risk behaviors associated with a new STI in this population after the repeal of "Don't Ask, Don't Tell." US Military HIV Natural History Study participants who completed the risk behavior questionnaire (RBQ) between 2014 and 2017 and had at least 1 year of follow-up were included ( n  = 1589). Logistic regression identified behaviors associated with incident STI in the year following RBQ completion. Overall, 18.9% acquired an STI and 52.7% reported condom use at last sexual encounter. Compared with those with no new sex partners, participants with between one and four or five or more new partners were 1.71 [1.25-2.35] and 6.12 [3.47-10.79] times more likely to get an STI, respectively. Individuals reporting low or medium/high perceived risk of STI were 1.83 [1.23-2.72] and 2.65 [1.70-4.15] times more likely to acquire a new STI than those reporting no perceived risk, respectively. Participants who preferred not to answer about sexual preference, number of new partners, or perceived STI risk were also more likely to acquire a new STI. Our study illustrates that despite regular access to health care and accurate perceptions of risk, rates of STI among PLWH remain high in the US military setting, as in others. Given the potential individual and public health consequences of STI coinfection after HIV, more work is needed to assess interventions aimed at sexual behavior change for PLWH.

Background: Infectious diseases pose a significant threat to health and readiness of military personnel deployed globally during wartime and peacekeeping activities. Surveillance and improvement in mitigation through research of infectious disease threats remain an integral part of Force Health Protection. Herein, we review research efforts of the Infectious Disease Clinical Research Program related to deployment and travel-related infections., Methods: The objectives of the Deployment and Travel-Related Infections Research Area are to (1) provide epidemiologic and clinical data, including pathogen-specific estimates of disease incidence among deployed troops, (2) execute clinical trials and effectiveness studies to improve recommendations regarding prevention and treatment of infections during deployment, and (3) evaluate the knowledge and practice patterns of health care providers engaged in deployment/travel medicine and the impact on outcomes. The centerpiece protocol of the research area is the Deployment and Travel-Related Infectious Disease Risk Assessment, Outcomes, and Prevention Strategies cohort study (TravMil), which was initiated in 2010 and collects data on a broad range of deployment-related infections., Results: To date, 4,154 deployed military personnel and traveling Department of Defense (DoD) beneficiaries have been enrolled in TravMil. Surveillance data collected through the TravMil study provide assessment of deployment and travel-related infectious disease threats, and the effectiveness of mitigation strategies. The incidence of travelers' diarrhea, influenza-like illness, and undifferentiated febrile illness is 20.48%, 9.34%, and 6.16%, respectively. The cohort study also provides necessary infrastructure to execute clinical trials. The TrEAT TD clinical trial evaluated the effectiveness of single-dose antibiotic therapy for travelers' diarrhea in the deployed setting. When compared to levofloxacin, azithromycin was not inferior; however, inferiority was not demonstrated with use of single dose of rifaximin. The trial findings supported the development of a deployment-related health guideline for the management of acute diarrheal disease. A clinical trial evaluating the effectiveness of rifaximin for prevention for travelers' diarrhea (Prevent TD) is underway., Conclusions: The research area has proven its ability to conduct impactful research, including the development of field-expedient diagnostics, the largest DoD multi-site travelers' diarrhea randomized control trial in peacetime and combat settings, and informed Force Health Protection guidance. The research area continues to provide surveillance data to military commands via an established collaborative network of military treatment facilities, DoD laboratories (both within and outside the continental United States), foreign militaries, and academia. The conduct of clinical and translational research in a deployment setting presents significant challenges, most notably in recruitment/enrollment and compliance with study-related procedures during deployment., (© Association of Military Surgeons of the United States 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prosthetic breast implantation is a common surgical procedure for augmentation and reconstruction after mastectomy. The incidence of implant infection is 1% to 2.5% and is higher for reconstruction following mastectomy compared with augmentation. Most infections are caused by gram-positive pathogens, such as coagulase-negative staphylococci, Cutibacterium species, Staphylococcus aureus, and streptococci. Acute infections are usually associated with fever and breast pain, erythema, and drainage. Subacute infections may present with chronic pain, persistent drainage, failed healing of the incision site, or migration of the implant. Depending on severity of infection, patients are started on empiric intravenous or oral antibiotics and closely monitored., (Published by Elsevier Inc.)

Objectives: To assess the reliability, validity, and responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO©) scores for quantifying the presence and severity of influenza symptoms., Methods: An observational prospective cohort study of adults (≥18 years) with influenza-like illness in the United States, the United Kingdom, Mexico, and South America was conducted. Participants completed the 37-item draft FLU-PRO daily for up to 14 days. Item-level and factor analyses were used to remove items and determine factor structure. Reliability of the final tool was estimated using Cronbach α and intraclass correlation coefficients (2-day reliability). Convergent and known-groups validity and responsiveness were assessed using global assessments of influenza severity and return to usual health., Results: Of the 536 patients enrolled, 221 influenza-positive subjects comprised the analytical sample. The mean age of the patients was 40.7 years, 60.2% were women, and 59.7% were white. The final 32-item measure has six factors/domains (nose, throat, eyes, chest/respiratory, gastrointestinal, and body/systemic), with a higher order factor representing symptom severity overall (comparative fit index = 0.92; root mean square error of approximation = 0.06). Cronbach α was high (total = 0.92; domain range = 0.71-0.87); test-retest reliability (intraclass correlation coefficient, day 1-day 2) was 0.83 for total scores and 0.57 to 0.79 for domains. Day 1 FLU-PRO domain and total scores were moderately to highly correlated (≥0.30) with Patient Global Rating of Flu Severity (except nose and throat). Consistent with known-groups validity, scores differentiated severity groups on the basis of global rating (total: F = 57.2, P < 0.001; domains: F = 8.9-67.5, P < 0.001). Subjects reporting return to usual health showed significantly greater (P < 0.05) FLU-PRO score improvement by day 7 than did those who did not, suggesting score responsiveness., Conclusions: Results suggest that FLU-PRO scores are reliable, valid, and responsive to change in influenza-positive adults., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Posttreatment control of HIV infection is a rare phenomenon primarily described among those initiating treatment with antiretroviral therapy (ART) during early/acute HIV infection., Methods: We examined a large, well-characterized cohort of HIV-infected Department of Defense beneficiaries for the presence of posttreatment controllers (PTCs) whom we defined as individuals with sustained viral suppression for ≥6 months after discontinuation of ART. We defined those who became viremic within 6 months of discontinuing ART as rapid viremics (RVs) and compared demographic and clinical characteristics, CD4 counts, and viral loads prior, during, and after ART discontinuation between the 2 groups., Results: From a cohort of 6070 patients, we identified 95 who had been treated with ART for 2 years or more who subsequently discontinued ART and had viral load assessments available after discontinuation. Four (4.2%) of these 95 met our definition of PTC. The duration of viral suppression off of ART ranged from 267 to 1058 days with 1 of the 4 restarting ART without having redeveloped a significant viremia. All 4 patients initiated ART during chronic HIV infection. Demographic and clinical characteristics of PTCs were similar to RVs., Conclusions: While posttreatment control has predominantly been described among individuals who initiated ART in early/acute HIV infection, we identified 4 PTCs who started ART during chronic infection suggesting that posttreatment control also occurs among such patients. The rarity of PTCs identified in our cohort is consistent with reports from previous studies.

Background: Infectious diarrhea is a common problem among travelers. Expert guidelines recommend the prompt use of antibiotics for self-treatment of moderate or severe travelers' diarrhea (TD). There is limited data on whether travelers follow these self-treatment guidelines. We evaluated the risk factors associated with TD, the use of TD self-treatment, and the risk of irritable bowel syndrome (IBS) during travel., Methods: Department of Defense beneficiaries traveling outside the United States for ≤6.5 months were enrolled in a prospective cohort study. Participants received pre- and post-travel surveys, and could opt into a travel illness diary and follow-up surveys for symptoms of IBS. Standard definitions were used to assess for TD and IBS. Suboptimal self-treatment was defined as the use of antibiotics (with or without antidiarrheal agents) for mild TD, or the use of antidiarrheals alone or no self-treatment in cases of moderate or severe TD., Results: Twenty-four percent of participants (270/1,120) met the criteria for TD. The highest incidence was recorded in Africa [8.6 cases/100 person-weeks, 95% confidence interval (CI): 6.7-10.5]. Two hundred and twelve participants with TD provided information regarding severity and self-treatment: 89 (42%) had mild TD and 123 (58%) had moderate or severe TD. Moderate or severe TD was independently associated with suboptimal self-treatment [OR 10.4 (95% CI: 4.92-22.0)]. Time to last unformed stool did not differ between optimal and suboptimal self-treatment. IBS occurred in 4.5% (7/154) of TD cases and in 3.1% (16/516) of cases without TD (p = 0.39). Among TD cases, a lower incidence of IBS was noted in participants who took antibiotics [4.8% (5/105) vs 2.2% (1/46)] in those who did not, but the difference did not reach statistical significance (p = 0.60)., Conclusions: Our results suggest the underutilization of antibiotics in travelers with moderate or severe TD. Further studies are needed to systematically evaluate pre-travel instruction and traveler adherence to self-treatment guidelines, and the impact of suboptimal self-treatment on outcomes., (© 2014 International Society of Travel Medicine.)

Importance: There are limited prospective, controlled data evaluating survival in patients receiving early surgery vs medical therapy for prosthetic valve endocarditis (PVE)., Objective: To determine the in-hospital and 1-year mortality in patients with PVE who undergo valve replacement during index hospitalization compared with patients who receive medical therapy alone, after controlling for survival and treatment selection bias., Design, Setting, and Participants: Participants were enrolled between June 2000 and December 2006 in the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), a prospective, multinational, observational cohort of patients with infective endocarditis. Patients hospitalized with definite right- or left-sided PVE were included in the analysis. We evaluated the effect of treatment assignment on mortality, after adjusting for biases using a Cox proportional hazards model that included inverse probability of treatment weighting and surgery as a time-dependent covariate. The cohort was stratified by probability (propensity) for surgery, and outcomes were compared between the treatment groups within each stratum., Interventions: Valve replacement during index hospitalization (early surgery) vs medical therapy., Main Outcomes and Measures: In-hospital and 1-year mortality., Results: Of the 1025 patients with PVE, 490 patients (47.8%) underwent early surgery and 535 individuals (52.2%) received medical therapy alone. Compared with medical therapy, early surgery was associated with lower in-hospital mortality in the unadjusted analysis and after controlling for treatment selection bias (in-hospital mortality: hazard ratio [HR], 0.44 [95% CI, 0.38-0.52] and lower 1-year mortality: HR, 0.57 [95% CI, 0.49-0.67]). The lower mortality associated with surgery did not persist after adjustment for survivor bias (in-hospital mortality: HR, 0.90 [95% CI, 0.76-1.07] and 1-year mortality: HR, 1.04 [95% CI, 0.89-1.23]). Subgroup analysis indicated a lower in-hospital mortality with early surgery in the highest surgical propensity quintile (21.2% vs 37.5%; P = .03). At 1-year follow-up, the reduced mortality with surgery was observed in the fourth (24.8% vs 42.9%; P = .007) and fifth (27.9% vs 50.0%; P = .007) quintiles of surgical propensity., Conclusions and Relevance: Prosthetic valve endocarditis remains associated with a high 1-year mortality rate. After adjustment for differences in clinical characteristics and survival bias, early valve replacement was not associated with lower mortality compared with medical therapy in the overall cohort. Further studies are needed to define the effect and timing of surgery in patients with PVE who have indications for surgery.

The typical clinical presentation of several spotted fever group Rickettsia infections includes eschars. Clinical diagnosis of the condition is usually made by analysis of blood samples. We describe a more sensitive, noninvasive means of obtaining a sample for diagnosis by using an eschar swab specimen from patients infected with Rickettsia parkeri.

Changes in serologic status in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) co-infected individuals with either isolated anti-HBc or resolved HBV infection have been reported, but the frequency of clinically meaningful long-term serologic changes is not well-defined. This study therefore, examined longitudinal serologic status for hepatitis B surface antigen (HBsAg)-negative HIV/HBV co-infected participants in a large cohort. Among 5,222 cohort participants, 347 (7%) were initially isolated anti-HBc positive, and 1,073 (21%) had resolved HBV infection (concurrently reactive for anti-HBc and anti-HBs). Thirty-three (10%) of the 347 participants with isolated anti-HBc were later positive for HBsAg at least once, compared with 3 (0.3%) of those with resolved HBV (P < 0.001). A total of 14 participants became persistently positive for HBsAg and were thus classified as having late-onset chronic HBV infection at a median of 3.7 years after initial HBV diagnosis. For those initially with HBsAg-negative HIV/HBV co-infection, the rate of late-onset chronic HBV infection was 1.39/1,000 person-years. Those with late-onset chronic HBV infection experienced significant decreases in CD4 cell counts (P = 0.002) with a mean of 132 cells/µl at the time of late-onset chronic HBV infection, but no factor distinguished those who were positive for HBsAg only once from those that developed late-onset chronic HBV infection. Over a median of 2.9 years following late-onset chronic HBV infection, 3 of 14 subsequently lost HBsAg. The occurrence of late-onset chronic HBV infection in HBsAg negative HIV/HBV co-infected adults appears to be one important, albeit rare, clinical event seen almost exclusively in those with isolated anti-HBc and low CD4 cell count., (Copyright © 2011 Wiley-Liss, Inc.)

Introduction: In a recent randomized trial of Staphylococcus aureus bacteremia and native valve endocarditis, daptomycin was found not inferior to standard therapy. We summarized findings in the subgroup of patients with endocarditis according to the Duke criteria., Methods: Patients were randomly assigned to receive daptomycin 6 mg/kg/day or standard therapy (vancomycin 1g every 12h or antistaphylococcal penicillin 2g every 4h, both with gentamicin 1mg/kg every 8h for the first 4 days). The primary end point was success in the modified intent-to-treat population 6 weeks after the end of therapy., Results: Fifty-three patients were included: 35 with right-sided endocarditis (RIE) and 18 with left-sided endocarditis (LIE). The success rates in patients with RIE were similar between daptomycin and the comparator (42% vs 44%). Patients with RIE with septic pulmonary infarcts responded similarly to treatment with daptomycin and standard therapy (60% vs 67%). In the LIE population, treatment success rates were poor in both arms (11% vs 22%)., Conclusion: Daptomycin is an efficacious and well-tolerated alternative to standard therapy in the treatment of RIE. Patients with LIE had a poor outcome regardless of the treatment received. Daptomycin is also effective in treating endocarditis with septic pulmonary infarcts., (Copyright © 2009 Elsevier España, S.L. All rights reserved.)

The risk of intravascular cardiac device infection (ICDI) has increased significantly over the last decade and is rising faster than the corresponding increase in device implantations. ICDIs may consist of pocket infections, wire infections, wire infections complicated by endocarditis, or combinations of these. In this review, we examine the microbiology of ICDIs, focusing on the risk of developing ICDI following bloodstream infections with key pathogens such as Staphylococcus aureus, coagulase-negative staphylococci, enterococci, etc., as well as the pathophysiology of these infections.

The majority of HIV-1 infections are acquired sexually, and interventions to prevent sexual transmission are urgently needed to curb the growth of the HIV pandemic. The potential role of antiretroviral therapy in preventing sexual transmission of HIV is still emerging. Highly active antiretroviral therapy has been shown to decrease HIV RNA shedding in the genital tract, and its use among serodiscordant couples has been associated with reduced seroconversions in partners who are HIV negative. However, other studies have associated the use of antiretroviral therapy with increased HIV transmission risk behaviors. In this review, we explore the rationale for using highly active antiretroviral therapy to prevent sexual transmission of HIV including its role in prevention strategies at the population level, as well as the cost-effectiveness and potential limitations of this approach.

The majority of HIV-1 infections are acquired sexually, and interventions to prevent sexual transmission are urgently needed to curb the growth of the HIV pandemic. The potential role of antiretroviral therapy in preventing sexual transmission of HIV is still emerging. Highly active antiretroviral therapy has been shown to decrease HIV RNA shedding in the genital tract, and its use among serodiscordant couples has been associated with reduced seroconversions in partners who are HIV negative. However, other studies have associated the use of antiretroviral therapy with increased HIV transmission risk behaviors. In this review, we explore the rationale for using highly active antiretroviral therapy to prevent sexual transmission of HIV including its role in prevention strategies at the population level, as well as the cost-effectiveness and potential limitations of this approach.