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(n = 150) Nonbattle injury (NBI) continues to be a leading cause of morbidity among troops currently deployed to Iraq and Afghanistan. To assess NBI incidence, impact, and risk factors, a survey was given to soldiers during mid- or postdeployment from Iraq, Afghanistan, and surrounding region, from January 2005 through May 2006. Among 3,367 troops completing a survey, 19.5% reported at least one NBI, and 85% sought care at least once for their symptoms. Service component, rank, and unit type were among factors associated with differential NBI risk. Twenty percent stated that NBI resulted in back-up personnel being called or shift change to cover impacted duties, and among those reported having been grounded from flight status, a third were the result of NBI. NBI continues to be a problem in recent deployments, and given the findings on individual and potential operational impact indicators, NBI should be viewed as a primary force health protection problem. [ABSTRACT FROM AUTHOR]

Background and Methods: Vector-borne diseases are known threats to deployed troops. We performed a cross-sectional study of troops deployed to Southwest Asia between January 2005 and February 2007 to evaluate practices of personal protective measures and their relationship to self-report of Old World cutaneous leishmaniasis (CL), a marker of vector-borne disease threat.Results: Regular or always N, N-diethyl-m-toluamide (DEET) use was low (2-5%). Associations for DEET use were command emphasis, branch of service, uniform treatment with permethrin, and duty station. Uniform treatment with permethrin was associated with branch of service, command emphasis, and use of DEET. We identified 22 cases of CL (incidence density of 1.8-3.7 per 100 person-years) with increased risk among Reserve/National Guard components, Air Force and Marine personnel.Conclusions: Commanders can influence the use of the military insect repellent system. Unit-based treatment of uniforms improves prevalence. CL incidence may be higher than previously reported. [ABSTRACT FROM AUTHOR]

The Current Topics in Military Tropical Medicine series provides focused reviews addressing specific questions faced by operational military medical personnel. This issue in the series explores the diagnosis and management of persistent diarrhea in deployed service members. [ABSTRACT FROM AUTHOR]

Much has been written about injury, diarrhea, and respiratory cases but less is known about other threats, specifically snake, scorpion, and spider encounters. To examine the risk from local fauna, a cross-sectional study using an anonymous survey was conducted among U.S. troops in Southwest Asia between January 2005 and May 2006. Among 3,265 troops, 9 cases (0.3%) of snakebites and 85 cases (2.6%) of spider stings and scorpion bites were reported, equating to an incidence of 46.1 per 10,000 person-months for scorpion/spider encounters and 4.9 per 10,000 person-months for snakebites. There was a significant association with service branch and toileting facilities for snakebites. Season, deployment location, rank, and toileting facilities were associated with differential risk of scorpion/spider encounters. Troops are at risk for local fauna encounters while deployed in the current operational environment. The potential morbidity, mortality, and operational impact of these health hazards need to be considered. [ABSTRACT FROM AUTHOR]

Background: Available data on combat wound-related invasive mould infections (IMIs) are limited., Objectives: We aimed to describe the characteristics and outcomes of IMIs in casualties of a recent conflict., Patients/methods: A retrospective study including hospitalised patients with combat-related injuries, fulfilling criteria for wound-related IMI based on Trauma Infectious Disease Outcomes Study definitions. Patient and injury characteristics, management and outcomes are described and compared to previous cohorts. Mould isolates and susceptibility testing results, including the novel agent manogepix, are reported., Results: Overall, 31 patients (69 mould isolates) were included-resulting in an IMI incidence rate of 1.9%. Blast was the most common injury mechanism (71%), with limb amputations and abdominoperineal injuries in 35% and 45%, respectively. Mould cultures, obtained mostly from lower extremities wounds (62%), were positive in all patients. Most (68%) had poly-mould infections, with Aspergillus and Fusarium species predominating. Overall, non-susceptibility rates of > 50% to newer azoles and 38% to amphotericin B reflected the high proportion of Fusarium spp., A. terreus and A. flavus, with the lowest azole minimal inhibitory concentrations demonstrated with posaconazole. Manogepix displayed good in-vitro activity against all isolates, except for Mucorales species. Two patients (6.5%) died of disseminated IMIs and 19% required amputations. Patients with Mucorales had poorer outcomes (40% mortality/amputation vs. 19% for non-Mucorales)., Conclusions: Combat wound-related IMIs are uncommon but carry significant morbidity and mortality. High susceptibility rates to manogepix were observed. Further studies are needed to evaluate optimal surgical approaches and the role of antifungal susceptibility testing in this setting., (© 2025 The Author(s). Mycoses published by Wiley‐VCH GmbH.)

Introduction: Vaccine mandates have been used to minimize the duty days lost and deaths attributable to infectious disease among active duty Service members (ADSMs). In response to the global COVID-19 pandemic, in August 2021, the U.S. DoD issued a COVID-19 vaccine mandate for all ADSMs. This study aimed to investigate COVID-19 vaccine uptake among the ADSM population, as well as factors associated with timing of COVID-19 vaccine receipt., Materials and Methods: This study included ADSMs on active duty between January 1, 2020, and June 30, 2022. Univariate analyses investigated associations between demographic factors (age, sex, race, ethnicity, branch of service, rank, and state of residence) and COVID-19 diagnosis with the following outcomes: (1) time to primary series initiation in relation to the DoD vaccine mandate, (2) time between doses of the 2-dose primary series, and (3) time between booster eligibility and receipt. This research received an exempt determination by the USU Human Research Protection Program., Results: In total, 1,799,466 ADSMs were included, with 90% receiving ≥1 COVID-19 vaccine dose during the study period and 77% initiating the primary series prior to the mandate. Over 80% of ADSMs received a complete primary series, with 96% of those adhering to the recommended regimen. The history of COVID-19 diagnosis was associated with the later receipt of all doses., Conclusions: COVID-19 vaccine uptake was high among all ADSMs, with the majority initiating the primary series before the mandate. The high vaccine uptake among ADSMs shown here may be used as a guide to both military and civilian pandemic policy and outreach efforts related to enhanced vaccine uptake., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2025. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Infections are the most frequent complication and cause of mortality in burn patients. We describe the epidemiology and outcomes of infections among deployed U.S. military personnel with burns., Methods: Military personnel who sustained a burn injury in Iraq or Afghanistan (2009-2014) and were admitted to the Burn Center at U.S. Army Institute of Surgical Research at Brooke Army Medical Center were included in the analysis., Results: The study population included 144 patients who were primarily young (median 24 years) males (99 %) with combat-related burns (62 %) sustained via a blast (57 %), resulting in a median total body surface area burned (TBSA) of 6 % (IQR 3-14 %). Twenty-six (18 %) patients developed infections, with pneumonia being the predominant initial infection (= 16), followed by skin and soft-tissue infections (SSTI, = 6), bloodstream infections (BSI, = 3), and intra-abdominal infections (IAI, = 1). Initial infections were diagnosed at a median of 4 days (IQR 3-5) post-injury for pneumonia, 7 days (IQR 4-12) for SSTIs, 7 days (IQR 6-7) for BSI, and 17 days for IAI. Patients with infections were more severely injured with greater TBSA (median 31 % vs 5 %), more inhalation injury (38 % vs 12 %), and longer time to definitive surgical management (median of 34 days vs 9) compared to those who did not develop infections (p < 0.001). Among patients with inhalation injury, a higher proportion developed pneumonia (42 %) compared to those without inhalation injury (5 %; p < 0.001). Five patients developed an invasive fungal infection. Gram-negative bacilli were most frequently recovered, with 32 % of Gram-negative isolates being multidrug-resistant. Four patients died, of whom all had ≥ 4 infections., Conclusions: Military personnel with burn injuries who developed infections were more severely injured with greater TBSA and inhalation injury. Improved understanding of risk factors for burn-related infections in combat casualties is critical for effective management., Competing Interests: Declaration of Competing Interest The authors have no conflicts to disclose. All authors approved the final version for submission., (Published by Elsevier Ltd.)

Introduction: The long-term impact of deployment-related trauma on mental and physical health-related quality of life (HRQoL) among military personnel is not well understood. We describe the mental and physical HRQoL among military personnel following deployment-related polytrauma after their discharge from the hospital and examine factors associated with HRQoL and longitudinal trends., Materials and Methods: The U.S. military personnel with battlefield-related trauma enrolled in the Trauma Infectious Diseases Outcomes Study were surveyed using SF-8 Health Surveys at 1 month post-discharge (baseline) and at follow-up intervals over 2 years. Inclusion in the longitudinal analysis required baseline SF-8 plus responses during early (3 and/or 6 months) and later follow-up periods (12, 18, and/or 24 months). Associations of demographics, injury characteristics, and hospitalization with baseline SF-8 scores and longitudinal changes in SF-8 scores during follow-up were examined. Survey responses were used to calculate the Mental Component Summary score (MCS) and the Physical Component Summary score (PCS). The MCS focuses on vitality, mental health, social functioning, and daily activity limitations, whereas PCS is related to general health, bodily pain, physical functioning, and physical activity limitations. Longitudinal trends in SF-8 scores were assessed using chi-square tests by comparing the median score at each timepoint to the median 1-month (baseline) score, as well as comparing follow-up scores to the immediately prior timepoint (e.g., 6 months vs. 3 months). Associations with the 1-month baseline SF-8 scores were assessed using generalized linear regression modeling and associations with longitudinal changes in SF-8 were examined using generalized linear regression modeling with repeated measures., Results: Among 781 enrollees, lower baseline SF-8 total scores and PCS were associated with spinal and lower extremity injuries (P < .001) in the multivariate analyses, whereas lower baseline MCS was associated with head/face/neck injuries (P < .001). Higher baseline SF-8 total was associated with having an amputation (P = .009), and lower baseline SF-8 total was also associated with sustaining a traumatic brain injury (TBI; P = .042). Among 524 enrollees with longitudinal follow-up, SF-8 scores increased, driven by increased PCS and offset by small MCS decreases. Upward SF-8 total score and PCS trends were associated with time post-hospital discharge and limb amputation (any) in the multivariate analyses (P < .05), whereas downward trends were independently associated with spinal injury and developing any post-discharge infection (P ≤ .001). Patients with lower extremity injuries had lower-magnitude improvements in PCS over time compared to those without lower extremity injuries (P < .001). Upward MCS trend was associated with higher injury severity (P = .003) in the multivariate analyses, whereas downward trends were independently associated with having a TBI (P < .001), time post-hospital discharge (P < .001), and occurrence of post-discharge infections (P = .002)., Conclusions: Overall, HRQoL increased during the 2-year follow-up period, driven by PCS improvement. Increasing HRQoL was associated with time since hospital discharge and limb amputation, whereas a downward trend in HRQoL was associated with spinal injury and post-discharge infection. The longitudinal decline in MCS, driven by TBI occurrence, time since hospital discharge, and developing post-discharge infections, emphasizes the importance of longitudinal mental health care in this population., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Combat casualties are frequently injured in austere settings where modern imaging modalities are unavailable. Exploratory laparotomies are often performed in these settings when there is suspicion for intra-abdominal injury. Prior studies of combat casualties reported non-therapeutic laparotomy (NTL) rates as high as 32%. Given improvements in combat casualty care over time, we evaluated NTLs performed during later years of the wars in Iraq and Afghanistan., Methods: Military personnel with combat-related injuries (6/1/2009-12/31/2014) who underwent exploratory laparotomy based on concern for abdominal injury (i.e. not performed for proximal vascular control or fecal diversion) and were evacuated to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals were assessed. An NTL was defined as a negative laparotomy without substantial intra-abdominal injuries requiring repair. Characteristics, indications for laparotomy, operative findings, and outcomes were examined., Results: Among 244 patients who underwent laparotomies, 41 (16.8%) had NTLs and 203 (83.2%) had therapeutic laparotomies (i.e. positive findings). Patients with NTLs had more computed tomography scans concerning for injury (48.8% vs 27.1%; p = 0.006), less penetrating injury mechanisms (43.9% vs 71.9%; p < 0.001), and lower Injury Severity Scores (26 vs 33; p = 0.003) compared to patients with therapeutic laparotomies. Patients with NTLs were also less likely to be admitted to the intensive care unit (70.7 vs 89.2% for patients with therapeutic laparotomies; p = 0.007). No patients with NTLs developed abdominal surgical site infections (SSI) compared to 16.7% of patients with therapeutic laparotomies (p = 0.002). There was no significant difference in mortality between the groups (p = 0.198)., Conclusions: Our proportion of NTLs was lower than reported from earlier years during the wars in Iraq and Afghanistan. No infectious complications from NTLs (i.e. abdominal SSIs) were identified. Nevertheless, surgeons should continue to have a low threshold for exploratory laparotomy in military patients in austere settings with concern for intra-abdominal injury., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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.)

Introduction: Military trainees are at increased risk for infectious disease outbreaks because of the unique circumstances of the training environment (e.g., close proximity areas and physiologic/psychologic stress). Standard medical countermeasures in military training settings include routine immunization (e.g., influenza and adenovirus) as well as chemoprophylaxis [e.g., benzathine penicillin G (Bicillin) for the prevention of group A streptococcal disease] for pathogens associated with outbreaks in these settings. In a population of U.S. Army Infantry trainees, we evaluated changes in the oral microbiome during a 14-week military training cycle., Materials and Methods: Trainees were enrolled in an observational cohort study in 2015-2016. In 2015, Bicillin was administered to trainees to ameliorate the risk of group A Streptococcus outbreaks, whereas in 2016, trainees did not receive a Bicillin inoculation. Oropharyngeal swabs were collected from participants at days 0, 7, 14, 28, 56, and 90 of training. Swabs were collected, flash frozen, and stored. DNA was extracted from swabs, and amplicon sequencing of the 16s rRNA gene was performed. Microbiome dynamics were evaluated using the QIIME 2 workflow along with DADA2, SINA with SILVA, and an additional processing in R., Results: We observed that microbiome samples from the baseline (day 0) visit were distinct from one another, whereas samples collected on day 14 exhibited significant microbiome convergence. Day 14 convergence was coincident with an increase in DNA sequences associated with Streptococcus, though there was not a significant difference between Streptococcus abundance over time between 2015 and 2016 (P = .07), suggesting that Bicillin prophylaxis did not significantly impact overall Streptococcus abundance., Conclusions: The temporary convergence of microbiomes is coincident with a rise in communicable infections in this population. The dynamic response of microbiomes during initial military training supports similar observations in the literature of transient convergence of the human microbiome under cohabitation in the time frame including in this experiment. This population and the associated longitudinal studies allow for controlled studies of human microbiome under diverse conditions., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Introduction: We sought to determine pre-infection correlates of protection against SARS-CoV-2 post-vaccine inzfections (PVI) acquired during the first Omicron wave in the United States., Methods: Serum and saliva samples from 176 vaccinated adults were collected from October to December of 2021, immediately before the Omicron wave, and assessed for SARS-CoV-2 Spike-specific IgG and IgA binding antibodies (bAb). Sera were also assessed for bAb using commercial assays, and for neutralization activity against several SARS-CoV-2 variants. PVI duration and severity, as well as risk and precautionary behaviors, were assessed by questionnaires., Results: Serum anti-Spike IgG levels assessed by research assay, neutralization titers against Omicron subvariants, and low home risk scores correlated with protection against PVIs after multivariable regression analysis. Commercial assays did not perform as well as research assay, likely due to their lower dynamic range., Discussion: In the 32 participants that developed PVI, anti-Spike IgG bAbs correlated with lower disease severity and shorter duration of illness., Competing Interests: SP, TB, and DT report that the USU IDCRP, a U.S. Department of Defense DoD 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 DoD 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 USG COVID-19 response. Neither is related to the work presented here. Authors WM and SA were employed by the company Quest Diagnostics. Author JP was employed by company Leidos Biomedical Research, Inc. Authors LV, MF, AL and FM were employed by company Leidos. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Goguet, Olsen, Meyer, Ansari, Powers, Conner, Coggins, Wang, Wang, Illinik, Sanchez Edwards, Jackson-Thompson, Hollis-Perry, Wang, Alcorta, Wong, Saunders, Mohammed, Balogun, Kobi, Kosh, Bishop-Lilly, Cer, Arnold, Voegtly, Fitzpatrick, Luquette, Malagon, Ortega, Parmelee, Davies, Lindrose, Haines-Hull, Moser, Samuels, Rekedal, Graydon, Malloy, Tribble, Burgess, Campbell, Robinson, Broder, O’Connell, Weiss, Pollett, Laing and Mitre.)

Background: Among combat injured, invasive fungal infections (IFIs) result in significant morbidity. Cultures and histopathology are the primary diagnostic methods for IFIs, but they have limitations. We previously evaluated a panfungal polymerase chain reaction assay, which was 83% sensitive and 99% specific for angioinvasive IFIs. Here, we evaluated 3 less resource-intensive seminested assays targeting clinically relevant fungi in the order Mucorales and genera Aspergillus and Fusarium ., Methods: Formalin-fixed paraffin-embedded tissue specimens from a multicenter trauma IFI cohort (2009-2014) were used. Cases were US military personnel injured in Afghanistan with histopathologic IFI evidence. Controls were patients with similar injury patterns and no laboratory IFI evidence (negative culture and histopathology). Seminested assays specific to Mucorales (V4/V5 regions of 18S rDNA), Aspergillus (mitochondrial tRNA), and Fusarium (internal transcribed spacer [ITS]/28A regions of DNA) were compared with a panfungal assay amplifying the internal transcribed spacer 2 region of rDNA and to histopathology., Results: Specimens from 92 injury sites (62 subjects) were compared with control specimens from 117 injuries (101 subjects). We observed substantial agreement between the seminested and panfungal assays overall, especially for the order Mucorales. Moderate agreement was observed at the genus level for Aspergillus and Fusarium . When compared with histopathology, sensitivity and specificity of seminested assays were 67.4% and 96.6%, respectively (sensitivity increased to 91.7% when restricted to sites with angioinvasion)., Conclusions: Prior studies of seminested molecular diagnostics have focused on culture-negative samples from immunocompromised patients. Our findings underscore the utility of the seminested approach in diagnosing soft-tissue IFIs using formalin-fixed paraffin-embedded tissue samples, especially with angioinvasion., Competing Interests: Potential conflicts of interest. The authors have no conflicts to declare., (© 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.

Background: People living in close quarters, such as military trainees, are at increased risk for skin and soft tissue infections (SSTI), especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). The serum immune factors associated with the onset of SSTI are not well understood., Methods: We conducted a longitudinal study of SSTIs, enrolling US Army trainees before starting military training and following up for 14 weeks. Samples were collected on Day 0, 56, and 90. Serum chemokines and cytokines among 16 SSTI cases and 51 healthy controls were evaluated using an electro-chemiluminescence based multiplex assay platform., Results: Of 54 tested cytokines, 12 were significantly higher among SSTI cases as compared to controls. Among the cases, there were correlations between factors associated with vascular injury (i.e., VCAM-1, ICAM-1, and Flt1), the angiogenetic factor VEGF, and IL-10. Unsupervised machine learning (Principal Component Analysis) revealed that IL10, IL17A, C-reactive protein, ICAM1, VCAM1, SAA, Flt1, and VGEF were indicative of SSTI., Conclusion: The study demonstrates the power of immunoprofiling for identifying factors predictive of pre-illness state of SSTI thereby identifying early stages of an infection and individuals susceptible to SSTI., Competing Interests: EM and KM were employed by Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Bergmann-Leitner, Millar, Duncan, Tribble, Carey, Ellis, Mende, Bennett and Chaudhury.)

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.)

Introduction: Battlefield-related wound infections are a significant source of morbidity among combat casualties. Seasonality of these infections was demonstrated in previous conflicts (e.g., Korea) but has not been described with trauma-related health care-associated infections from the war in Afghanistan., Methods: The study population included military personnel wounded in Afghanistan (2009-2014) medevac'd to Landstuhl Regional Medical Center and transitioned to participating military hospitals in the United States with clinical suspicion of wound infections and wound cultures collected ≤7 days post-injury. Analysis was limited to the first wound culture from individuals. Infecting isolates were collected from skin and soft-tissue infections, osteomyelitis, and burn soft-tissue infections. Data were analyzed by season (winter [ December 1-February 28/29], spring [March 1-May 31], summer [June 1-August 31], and fall [September 1-November 30])., Results: Among 316 patients, 297 (94.0%) sustained blast injuries with a median injury severity score and days from injury to initial culture of 33 and 3.5, respectively. Although all patients had a clinical suspicion of a wound infection, a diagnosis was confirmed in 198 (63%) patients. Gram-negative bacilli (59.5% of 316) were more commonly isolated from wound cultures in summer (68.1%) and fall (67.1%) versus winter (43.9%) and spring (45.1%; P < .001). Multidrug-resistant (MDR) Gram-negative bacilli (21.8%) were more common in summer (21.8%) and fall (30.6%) versus winter (7.3%) and spring (19.7%; P = .028). Findings were similar for infecting Gram-negative bacilli (72.7% of 198)-summer (79.5%) and fall (83.6%; P = .001)-and infecting MDR Gram-negative bacilli (27.3% of 198)-summer (25.6%) and fall (41.8%; P = .015). Infecting anaerobes were more common in winter (40%) compared to fall (11%; P = .036). Gram-positive organisms were not significantly different by season., Conclusion: Gram-negative bacilli, including infecting MDR Gram-negative bacilli, were more commonly recovered in summer/fall months from service members injured in Afghanistan. This may have implications for empiric antibiotic coverage during these months., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

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.)

Enterobacter cloacae is a Gram-negative rod with multidrug-resistant potential due to chromosomally-induced AmpC β-lactamase. We evaluated characteristics, antibiotic utilization, and outcomes associated with battlefield-related E. cloacae infections (2009-2014). Single initial and serial E. cloacae isolates (≥24 hours from initial isolate from any site) associated with a clinical infection were examined. Susceptibility profiles of initial isolates in the serial isolation group were contrasted against last isolate recovered. Characteristics of 112 patients with E. cloacae infections (63 [56%] with single initial isolation; 49 [44%] with serial isolation) were compared to 509 patients with bacterial infections not attributed to E. cloacae. E. cloacae patients sustained more blast trauma (78%) compared to non-E. cloacae infections patients (75%; p<0.001); however, injury severity scores were comparable (median of 34.5 and 33, respectively; p = 0.334). Patients with E. cloacae infections had greater shock indices (median 1.07 vs 0.92; p = 0.005) and required more initial blood products (15 vs. 14 units; p = 0.032) compared to patients with non-E. cloacae infections. Although E. cloacae patients had less intensive care unit admissions (80% vs. 90% with non-E. cloacae infection patients; p = 0.007), they did have more operating room visits (5 vs. 4; p = 0.001), longer duration of antibiotic therapy (43.5 vs. 34 days; p<0.001), and lengthier hospitalizations (57 vs. 44 days; p<0.001). Patients with serial E. cloacae had isolation of infecting isolates sooner than patients with single initial E. cloacae (median of 5 vs. 8 days post-injury; p = 0.046); however, outcomes were not significantly different between the groups. Statistically significant resistance to individual antibiotics did not develop between initial and last isolates in the serial isolation group. Despite current combat care and surgical prophylaxis guidelines recommending upfront provision of AmpC-inducing antibiotics, clinical outcomes did not differ nor did significant antibiotic resistance develop in patients who experienced serial isolation of E. cloacae versus single initial isolation., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KM, LS, FS, and AR are/were employees of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF), a not-for-profit Foundation authorized by Congress to support research at the Uniformed Services University of the Health Sciences (USU) and throughout military medicine. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Please see Data Availability Statement., (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: Penetrating brain injuries are a potentially lethal injury associated with substantial morbidity and mortality. We examined characteristics and outcomes among military personnel who sustained battlefield-related open and penetrating cranial injuries during military conflicts in Iraq and Afghanistan., Methods: Military personnel wounded during deployment (2009-2014) were included if they sustained an open or penetrating cranial injury and were admitted to participating hospitals in the United States. Injury characteristics, treatment course, neurosurgical interventions, antibiotic use, and infection profiles were examined., Results: The study population included 106 wounded personnel, of whom 12 (11.3%) had an intracranial infection. Posttrauma prophylactic antibiotics were prescribed in more than 98% of patients. Patients who developed central nervous system (CNS) infections were more likely to have undergone a ventriculostomy ( p = 0.003), had a ventriculostomy in place for a longer period (17 vs. 11 days; p = 0.007), had more neurosurgical procedures ( p < 0.001), and have lower presenting Glasgow Coma Scale ( p = 0.01) and higher Sequential Organ Failure Assessment scores ( p = 0.018). Time to diagnosis of CNS infection was a median of 12 days postinjury (interquartile range, 7-22 days) with differences in timing by injury severity (critical head injury had median of 6 days, while maximal [currently untreatable] head injury had a median of 13.5 days), presence of other injury profiles in addition to head/face/neck (median, 22 days), and the presence of other infections in addition to CNS infections (median, 13.5 days). The overall length of hospitalization was a median of 50 days, and two patients died., Conclusion: Approximately 11% of wounded military personnel with open and penetrating cranial injuries developed CNS infections. These patients were more critically injured (e.g., lower Glasgow Coma Scale and higher Sequential Organ Failure Assessment scores) and required more invasive neurosurgical procedures., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2023 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles., Methods: 1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations., Results: We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 ("Nasal cluster") is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 ("Sensory cluster") is highly correlated with loss of smell or taste, and cluster 3 ("Respiratory/Systemic cluster") is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01)., Conclusions: We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk., 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) 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.)

Importance: Understanding the factors associated with post-COVID conditions is important for prevention., Objective: To identify characteristics associated with persistent post-COVID-19 symptoms and to describe post-COVID-19 medical encounters., Design, Setting, and Participants: This cohort study used data from the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential (EPICC) study implemented in the US military health system (MHS); MHS beneficiaries aged 18 years or older who tested positive for SARS-CoV-2 from February 28, 2020, through December 31, 2021, were analyzed, with 1-year follow-up., Exposures: SARS-CoV-2 infection., Main Outcomes and Measures: The outcomes analyzed included survey-reported symptoms through 6 months after SARS-CoV-2 infection and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis categories reported in medical records 6 months following SARS-CoV-2 infection vs 3 months before infection., Results: More than half of the 1832 participants in these analyses were aged 18 to 44 years (1226 [66.9%]; mean [SD] age, 40.5 [13.7] years), were male (1118 [61.0%]), were unvaccinated at the time of their infection (1413 [77.1%]), and had no comorbidities (1290 [70.4%]). A total of 728 participants (39.7%) had illness that lasted 28 days or longer (28-89 days: 364 [19.9%]; ≥90 days: 364 [19.9%]). Participants who were unvaccinated prior to infection (risk ratio [RR], 1.39; 95% CI, 1.04-1.85), reported moderate (RR, 1.80; 95% CI, 1.47-2.22) or severe (RR, 2.25; 95% CI, 1.80-2.81) initial illnesses, had more hospitalized days (RR per each day of hospitalization, 1.02; 95% CI, 1.00-1.03), and had a Charlson Comorbidity Index score of 5 or greater (RR, 1.55; 95% CI, 1.01-2.37) were more likely to report 28 or more days of symptoms. Among unvaccinated participants, postinfection vaccination was associated with a 41% lower risk of reporting symptoms at 6 months (RR, 0.59; 95% CI, 0.40-0.89). Participants had higher risk of pulmonary (RR, 2.00; 95% CI, 1.40-2.84), diabetes (RR, 1.46; 95% CI, 1.00-2.13), neurological (RR, 1.29; 95% CI, 1.02-1.64), and mental health-related medical encounters (RR, 1.28; 95% CI, 1.01-1.62) at 6 months after symptom onset than at baseline (before SARS-CoV-2 infection)., Conclusions and Relevance: In this cohort study, more severe acute illness, a higher Charlson Comorbidity Index score, and being unvaccinated were associated with a higher risk of reporting COVID-19 symptoms lasting 28 days or more. Participants with COVID-19 were more likely to seek medical care for diabetes, pulmonary, neurological, and mental health-related illness for at least 6 months after onset compared with their pre-COVID baseline health care use patterns. These findings may inform the risk-benefit ratio of COVID-19 vaccination policy.

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: Infection is a frequent and serious complication after combat-related trauma. The Sequential Organ Failure Assessment (SOFA) score has been shown to have predictive value for outcomes, including sepsis and mortality, among various populations. We evaluated the prognostic ability of SOFA score in a combat-related trauma population. Methods: Combat casualties (2009-2014) admitted to Landstuhl Regional Medical Center (LRMC; Germany) intensive care unit (ICU) within 4 days post-injury followed by transition to ICUs in military hospitals in the United States were included. Multivariate logistic regression was used to determine predictive effect of selected variables and receiver operating characteristic (ROC) curve analysis was used to evaluate overall accuracy of SOFA score for infection prediction. Results: Of the 748 patients who met inclusion criteria, 436 (58%) were diagnosed with an infection (32% bloodstream, 63% skin and soft tissue, and 40% pulmonary) and were predominantly young (median 24 years) males. Penetrating trauma accounted for 95% and 86% of injuries among those with and without infections, respectively (p < 0.001). Median LRMC admission SOFA score was 7 (interquartile range [IQR]: 4-9) in patients with infections versus 4 (IQR: 2-6) in patients without infections (p < 0.001). Thirty-day mortality was 2% in both groups. On multivariate regression, LRMC SOFA score was independently associated with infection development (odds ratio: 1.2; 95% confidence interval: 1.1-1.3). The ROC curve analysis revealed an area under the curve of 0.69 for infection prediction, and 0.80 for mortality prediction. Conclusions: The SOFA scores obtained up to 4 days post-injury predict late onset infection occurrence. This study revealed that for every 1 point increase in LRMC SOFA score, the odds of having an infection increases by a factor of 1.2, controlling for other predictors. The use of SOFA score in admission assessments may assist clinicians with identifying those at higher risk of infection following combat-related trauma.

The human microbiome is comprised of a complex and diverse community of organisms that is subject to dynamic changes over time. As such, cross-sectional studies of the microbiome provide a multitude of information for a specific body site at a particular time, but they fail to account for temporal changes in microbial constituents resulting from various factors. To address this shortcoming, longitudinal research studies of the human microbiome investigate the influence of various factors on the microbiome of individuals within a group or community setting. These studies are vital to address the effects of host and/or environmental factors on microbiome composition as well as the potential contribution of microbiome members during the course of an infection. The relationship between microbial constituents and disease development has been previously explored for skin and soft tissue infections (SSTIs) within congregate military trainees. Accordingly, approximately 25% of the population carries Staphylococcus aureus within their nasal cavity, and these colonized individuals are known to be at increased risk for SSTIs. To examine the evolution of the nasal microbiota of U.S. Army Infantry trainees, individuals were sampled longitudinally from their arrival at Fort Benning, Georgia, until completion of their training 90 days later. These samples were then processed to determine S. aureus colonization status and to profile the nasal microbiota using 16S rRNA gene-based methods. Microbiota stability differed dramatically among the individual trainees; some subjects exhibited great stability, some subjects showed gradual temporal changes and some subjects displayed a dramatic shift in nasal microbiota composition. Further analysis utilizing the available trainee metadata suggests that the major drivers of nasal microbiota stability may be S. aureus colonization status and geographic origin of the trainees. Nasal microbiota evolution within the congregate setting imposed by military training is a complex process that appears to be affected by numerous factors. This finding may indicate that future campaigns to prevent S. aureus colonization and future SSTIs among high-risk military trainees may require a 'personalized' approach., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Patient-reported outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are an important measure of the full burden of coronavirus disease (COVID). Here, we examine how (1) infecting genotype and COVID-19 vaccination correlate with inFLUenza Patient-Reported Outcome (FLU-PRO) Plus score, including by symptom domains, and (2) FLU-PRO Plus scores predict return to usual activities and health., Methods: The ep idemiology, i mmunology, and c linical c haracteristics of pandemic infectious diseases (EPICC) study was implemented to describe the short- and long-term consequences of SARS-CoV-2 infection in a longitudinal, observational cohort. Multivariable linear regression models were run with FLU-PRO Plus scores as the outcome variable, and multivariable Cox proportional hazards models evaluated effects of FLU-PRO Plus scores on return to usual health or activities., Results: Among the 764 participants included in this analysis, 63% were 18-44 years old, 40% were female, and 51% were White. Being fully vaccinated was associated with lower total scores (β = -0.39; 95% CI, -0.57 to -0.21). The Delta variant was associated with higher total scores (β = 0.25; 95% CI, 0.05 to 0.45). Participants with higher FLU-PRO Plus scores were less likely to report returning to usual health and activities (health: hazard ratio [HR], 0.46; 95% CI, 0.37 to 0.57; activities: HR, 0.56; 95% CI, 0.47 to 0.67). Fully vaccinated participants were more likely to report returning to usual activities (HR, 1.24; 95% CI, 1.04 to 1.48)., Conclusions: Full SARS-CoV-2 vaccination is associated with decreased severity of patient-reported symptoms across multiple domains, which in turn is likely to be associated with earlier return to usual activities. In addition, infection with the Delta variant was associated with higher FLU-PRO Plus scores than previous variants, even after controlling for vaccination status., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2022.)

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.

Introduction: Extremity trauma is the most common battlefield injury, resulting in a high frequency of combat-related extremity wound infections (CEWIs). As these infections are associated with substantial morbidity and may impact wounded warriors long after initial hospitalization, CEWIs have been a focus of the Infectious Disease Clinical Research Program (IDCRP). Herein, we review findings of CEWI research conducted through the IDCRP and discuss future and ongoing analyses., Methods: Military personnel with deployment-related trauma sustained between 2009 and 2014 were examined in retrospective analyses through the observational Trauma Infectious Disease Outcomes Study (TIDOS). Characteristics of wounded warriors with ≥1 open extremity wound were assessed, focusing on injury patterns and infection risk factors. Through a separate trauma-associated osteomyelitis study, military personnel with combat-related open fractures of the long bones (tibia, femur, and upper extremity) sustained between 2003 and 2009 were examined to identify osteomyelitis risk factors., Results: Among 1,271 wounded warriors with ≥1 open extremity wound, 16% were diagnosed with a CEWI. When assessed by their most severe extremity injury (i.e., amputation, open fracture, or open soft-tissue wound), patients with amputations had the highest proportion of infections (47% of 212 patients with traumatic amputations). Factors related to injury pattern, mechanism, and severity were independent predictors of CEWIs during initial hospitalization. Having a non-extremity infection at least 4 days before CEWI diagnosis was associated with reduced likelihood of CEWI development. After hospital discharge, 28% of patients with extremity trauma had a new or recurrent CEWI during follow-up. Risk factors for the development of CEWIs during follow-up included injury pattern, having either a CEWI or other infection during initial hospitalization, and receipt of antipseudomonal penicillin for ≥7 days. A reduced likelihood for CEWIs during follow-up was associated with a hospitalization duration of 15-30 days. Under the retrospective osteomyelitis risk factor analysis, patients developing osteomyelitis had higher open fracture severity based on Gustilo-Anderson (GA) and the Orthopaedic Trauma Association classification schemes and more frequent traumatic amputations compared to open fracture patients without osteomyelitis. Recurrence of osteomyelitis was also common (28% of patients with open tibia fractures had a recurrent episode). Although osteomyelitis risk factors differed between the tibia, femur, and upper extremity groups, sustaining an amputation, use of antibiotic beads, and being injured in the earlier years of the study (before significant practice pattern changes) were consistent predictors. Other risk factors included GA fracture severity ≥IIIb, blast injuries, foreign body at fracture site (with/without orthopedic implant), moderate/severe muscle damage and/or necrosis, and moderate/severe skin/soft-tissue damage. For upper extremity open fractures, initial stabilization following evacuation from the combat zone was associated with a reduced likelihood of osteomyelitis., Conclusions: Forthcoming studies will examine the effectiveness of common antibiotic regimens for managing extremity deep soft-tissue infections to improve clinical outcomes of combat casualties and support development of clinical practice guidelines for CEWI treatment. The long-term impact of extremity trauma and resultant infections will be further investigated through both Department of Defense and Veterans Affairs follow-up, as well as examination of the impact on comorbidities and mental health/social factors., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The Joint Trauma System (JTS) is a DoD Center of Excellence for Military Health System trauma care delivery and the DoD's reference body for trauma care in accordance with National Defense Authorization Act for Fiscal Year 2017. Through the JTS, evidence-based clinical practice guidelines (CPGs) have been developed and subsequently refined to standardize and improve combat casualty care. Data are amassed through a single, centralized DoD Trauma Registry to support process improvement measures with specialty modules established as the registry evolved. Herein, we review the implementation of the JTS DoD Trauma Registry specialty Infectious Disease Module and the development of infection-related CPGs and summarize published findings on the subsequent impact of the Infectious Disease Module on combat casualty care clinical practice and guidelines., Methods: The DoD Trauma Registry Infectious Disease Module was developed in collaboration with the Infectious Disease Clinical Research Program (IDCRP) Trauma Infectious Disease Outcomes Study (TIDOS). Infection-related information (e.g., syndromes, antibiotic management, and microbiology) were collected from military personnel wounded during deployment June 1, 2009 through December 31, 2014 and medevac'd to Landstuhl Regional Medical Center in Germany before transitioning to participating military hospitals in the USA., Results: To support process improvements and reduce variation in practice patterns, data collected through the Infectious Disease Module have been utilized in TIDOS analyses focused on assessing compliance with post-trauma antibiotic prophylaxis recommendations detailed in JTS CPGs. Analyses examined compliance over three time periods: 6 months, one-year, and 5 years. The five-year analysis demonstrated significantly improved adherence to recommendations following the dissemination of the 2011 JTS CPG, particularly with open fractures (34% compliance compared to 73% in 2013-2014). Due to conflicting recommendations regarding use of expanded Gram-negative coverage with open fractures, infectious outcomes among patients with open fractures who received cefazolin or expanded Gram-negative coverage (cefazolin plus fluoroquinolones and/or aminoglycosides) were also examined in a TIDOS analysis. The lack of a difference in the proportion of osteomyelitis (8% in both groups) and the significantly greater recovery of Gram-negative organisms resistant to aminoglycosides or fluoroquinolones among patients who received expanded Gram-negative coverage supported JTS recommendations regarding the use of cefazolin with open fractures. Following recognition of the outbreak of invasive fungal wound infections (IFIs) among blast casualties injured in Afghanistan, the ID Module was refined to capture data (e.g., fungal culture and histopathology findings, wound necrosis, and antifungal management) needed for the TIDOS team to lead the DoD outbreak investigation. These data captured through the Infectious Disease Module provided support for the development of a JTS CPG for the prevention and management of IFIs, which was later refined based on subsequent TIDOS IFI analyses., Conclusions: To improve combat casualty care outcomes and mitigate high-consequence infections in future conflicts, particularly in the event of prolonged field care, expansion, refinement, and a mechanism for sustainability of the DoD Trauma Registry Infectious Disease Module is needed to include real-time surveillance of infectious disease trends and outcomes., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: In the aftermath of wars, there is a surge in the number of wounded service members who leave active duty and become eligible for healthcare through the Department of Veterans Affairs (VA). Collaborations between the Department of Defense (DoD) and VA are crucial to capture comprehensive data and further understand the long-term impact of battlefield trauma. We provide a summary of the development, methodology, and status of an effective collaboration between the Infectious Disease Clinical Research Program and the St. Louis VA Health Care System with the multicenter, observational Trauma Infectious Disease Outcomes Study (TIDOS), which examines the short- and long-term outcomes of deployment-related trauma., Methods: As part of TIDOS, wounded service members who transitioned to participating military hospitals in the United States (2009-2014) were given the opportunity to enroll in a prospective follow-up cohort study to continue to capture infection-related data after their hospital discharge. Enrollees in the TIDOS cohort who left military service and received health care through the VA also had the option of consenting to have relevant VA medical records abstracted and included with the study data. Infections considered to be complications resulting from the initial trauma were examined., Results: Among 1,336 TIDOS enrollees, 1,221 (91%) registered and received health care through the VA with 633 (47%) consenting to follow-up using VA records and comprising the TIDOS-VA cohort. Of the first 337 TIDOS-VA cohort enrollees, 38% were diagnosed with a new trauma-related infection following hospital discharge (median: 88 days; interquartile range: 18-351 days). Approximately 71% of the infections were identified through DoD sources (medical records and follow-up) and 29% were identified through VA electronic medical records, demonstrating the utility of DoD-VA collaborations. The TIDOS DoD-VA collaboration has also been utilized to assess intermediate and long-term consequences of specific injury patterns. Among 89 TIDOS-VA cohort enrollees with genitourinary trauma, 36% reported sexual dysfunction, 21% developed at least one urinary tract infection, 14% had urinary retention/incontinence, and 8% had urethral stricture. The rate of urinary tract infections was 0.05/patient-year during DoD follow-up time and 0.07/patient-year during VA follow-up time., Conclusions: Wider capture of infection-related outcome data through the DoD-VA collaboration provided a clearer picture of the long-term infection burden resulting from deployment-related trauma. Planned analyses include assessment of osteomyelitis among combat casualties with amputations and/or open fractures, evaluation of mental health and social factors related to injury patterns, and examination of health care utilization and cost in relation to infectious disease burdens., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Introduction: During the wars in Iraq and Afghanistan, increased incidence of multidrug-resistant (MDR) organisms, as well as polymicrobial wounds and infections, complicated the management of combat trauma-related infections. Multidrug resistance and wound microbiology are a research focus of the Trauma Infectious Disease Outcomes Study (TIDOS), an Infectious Disease Clinical Research Program, Uniformed Services University, research protocol. To conduct comprehensive microbiological research with the goal of improving the understanding of the complicated etiology of wound infections, the TIDOS MDR and Virulent Organisms Trauma Infections Initiative (MDR/VO Initiative) was established as a collaborative effort with the Brooke Army Medical Center, Naval Medical Research Center, U.S. Army Institute of Surgical Research, and Walter Reed Army Institute of Research. We provide a review of the TIDOS MDR/VO Initiative and summarize published findings., Methods: Antagonism and biofilm formation of commonly isolated wound bacteria (e.g., ESKAPE pathogens-Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), antimicrobial susceptibility patterns, and clinical outcomes are being examined. Isolates collected from admission surveillance swabs, as part of infection control policy, and clinical infection workups were retained in the TIDOS Microbiological Repository and associated clinical data in the TIDOS database., Results: Over the TIDOS study period (June 2009 to December 2014), more than 8,300 colonizing and infecting isolates were collected from military personnel injured with nearly one-third of isolates classified as MDR. At admission to participating U.S. military hospitals, 12% of wounded warriors were colonized with MDR Gram-negative bacilli. Furthermore, 27% of 913 combat casualties with ≥1 infection during their trauma hospitalization had MDR Gram-negative bacterial infections. Among 335 confirmed combat-related extremity wound infections (2009-2012), 61% were polymicrobial and comprised various combinations of Gram-negative and Gram-positive bacteria, yeast, fungi, and anaerobes. Escherichia coli was the most common Gram-negative bacilli isolated from clinical workups, as well as the most common colonizing MDR secondary to extended-spectrum β-lactamase resistance. Assessment of 479 E. coli isolates collected from wounded warriors found 188 pulsed-field types (PFTs) from colonizing isolates and 54 PFTs from infecting isolates without significant overlap across combat theaters, military hospitals, and study years. A minority of patients with colonizing E. coli isolates developed subsequent infections with the same E. coli strain. Enterococcus spp. were most commonly isolated from polymicrobial wound infections (53% of 204 polymicrobial cultures). Patients with Enterococcus infections were severely injured with a high proportion of lower extremity amputations and genitourinary injuries. Approximately 65% of polymicrobial Enterococcus infections had other ESKAPE organisms isolated. As biofilms have been suggested as a cause of delayed wound healing, wound infections with persistent recovery of bacteria (isolates of same organism collected ≥14 days apart) and nonrecurrent bacterial isolates were assessed. Biofilm production was significantly associated with recurrent bacteria isolation (97% vs. 59% with nonrecurrent isolates; P < 0.001); however, further analysis is needed to confirm biofilm formation as a predictor of persistent wound infections., Conclusions: The TIDOS MDR/VO Initiative provides comprehensive and detailed data of major microbial threats associated with combat-related wound infections to further the understanding of wound etiology and potentially identify infectious disease countermeasures, which may lead to improvements in combat casualty care., (© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: During Operation Enduring Freedom in Afghanistan, an outbreak of combat-related invasive fungal wound infections (IFIs) emerged among casualties with dismounted blast trauma and became a priority issue for the Military Health System., Methods: In 2011, the Trauma Infectious Disease Outcomes Study (TIDOS) team led the Department of Defense IFI outbreak investigation to describe characteristics of IFIs among combat casualties and provide recommendations related to management of the disease. To support the outbreak investigation, existing IFI definitions and classifications utilized for immunocompromised patients were modified for use in epidemiologic research in a trauma population. Following the conclusion of the outbreak investigation, multiple retrospective analyses using a population of 77 IFI patients (injured during June 2009 to August 2011) were conducted to evaluate IFI epidemiology, wound microbiology, and diagnostics to support refinement of Joint Trauma System (JTS) clinical practice guidelines. Following cessation of combat operations in Afghanistan, the TIDOS database was comprehensively reviewed to identify patients with laboratory evidence of a fungal infection and refine the IFI classification scheme to incorporate timing of laboratory fungal evidence and include categories that denote a high or low level of suspicion for IFI. The refined IFI classification scheme was utilized in a large-scale epidemiologic assessment of casualties injured over a 5.5-year period., Results: Among 720 combat casualties admitted to participating hospitals (2009-2014) who had histopathology and/or wound cultures collected, 94 (13%) met criteria for an IFI and 61 (8%) were classified as high suspicion of IFI. Risk factors for development of combat-related IFIs include sustaining a dismounted blast injury, experiencing a traumatic transfemoral amputation, and requiring resuscitation with large-volume (>20 units) blood transfusions. Moreover, TIDOS analyses demonstrated the adverse impact of IFIs on wound healing, particularly with order Mucorales. A polymerase chain reaction (PCR)-based assay to identify filamentous fungi and support earlier IFI diagnosis was also assessed using archived formalin-fixed, paraffin-embedded tissue specimens. Although the PCR-based assay had high specificity (99%), there was low sensitivity (63%); however, sensitivity improved to 83% in tissues collected from sites with angioinvasion. Data obtained from the initial IFI outbreak investigation (37 IFI patients) and subsequent TIDOS analyses (77 IFI patients) supported development and refinement of a JTS clinical practice guideline for the management of IFIs in war wounds. Furthermore, a local clinical practice guideline to screen for early tissue-based evidence of IFIs among blast casualties at the Landstuhl Regional Medical Center was critically evaluated through a TIDOS investigation, providing additional clinical practice support. Through a collaboration with the Uniformed Services University Surgical Critical Care Initiative, findings from TIDOS analyses were used to support development of a clinical decision support tool to facilitate early risk stratification., Conclusions: Combat-related IFIs are a highly morbid complication following severe blast trauma and remain a threat for future modern warfare. Our findings have supported JTS clinical recommendations, refined IFI classification, and confirmed the utility of PCR-based assays as a complement to histopathology and/or culture to promote early diagnosis. Analyses underway or planned will add to the knowledge base of IFI epidemiology, diagnostics, prevention, and management., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Intestinal anastomoses in military settings are performed in severely injured patients who often undergo damage control laparotomy in austere environments. We describe anastomotic outcomes of patients from recent wars., Methods: Military personnel with combat-related intra-abdominal injuries (June 2009-December 2014) requiring laparotomy with resection and anastomosis were analyzed. Patients were evacuated from Iraq or Afghanistan to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals., Results: Among 341 patients who underwent 1053 laparotomies, 87 (25.5%) required ≥1 anastomosis. Stapled anastomosis only was performed in 57.5% of patients, while hand-sewn only was performed in 14.9%, and 9.2% had both stapled and hand-sewn techniques (type unknown for 18.4%). Anastomotic failure occurred in 15% of patients. Those with anastomotic failure required more anastomoses (median 2 anastomoses, interquartile range [IQR] 1-3 vs. 1 anastomosis, IQR 1-2, P = .03) and more total laparotomies (median 5 laparotomies, IQR 3-12 vs. 3, IQR 2-4, P = .01). There were no leaks in patients that had only hand-sewn anastomoses, though a significant difference was not seen with those who had stapled anastomoses. While there was an increasing trend regarding surgical site infections (SSIs) with anastomotic failure after excluding superficial SSIs, it was not significant. There was no difference in mortality., Discussion: Military trauma patients have a similar anastomotic failure rate to civilian trauma patients. Patients with anastomotic failure were more likely to have had more anastomoses and more total laparotomies. No definitive conclusions can be drawn about anastomotic outcome differences between hand-sewn and stapled techniques.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies decay but persist 6 months postvaccination; lower levels of neutralizing titers persist against Delta than wild-type virus. Of 227 vaccinated healthcare workers tested, only 2 experienced outpatient symptomatic breakthrough infections, despite 59/227 exhibiting serologic evidence of SARS-CoV-2 infection, defined as presence of nucleocapsid protein antibodies.

Introduction: Multidrug-resistant (MDR) Gram-negative infections complicate care of combat casualties. We describe the clinical characteristics, resistance patterns, and outcomes of Pseudomonas aeruginosa infections in combat casualties., Methods: Combat casualties included in the Trauma Infectious Disease Outcomes Study with infections with and without P. aeruginosa isolation during initial hospitalization were compared. Pseudomonas aeruginosa from initial wound, blood, and serial isolates (≥7 days from previous isolate) collected from June 2009 through February 2014 was subjected to antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and whole genome sequencing for assessing clonality. Multidrug resistance was determined using the CDC National Healthcare Safety Network definition., Results: Of 829 combat casualties with infections diagnosed during initial hospitalization, 143 (17%) had P. aeruginosa isolated. Those with P. aeruginosa were more severely injured (median Injury Severity Score 33 [interquartile range (IQR) 27-45] vs 30 [IQR 18.5-42]; P < .001), had longer hospitalizations (median 58.5 [IQR 43-95] vs 38 [IQR 26-56] days; P < .001), and higher mortality (6.9% vs 1.5%; P < .001) than those with other organisms. Thirty-nine patients had serial P. aeruginosa isolation (median 2 subsequent isolates; IQR: 1-5), with decreasing antimicrobial susceptibility. Ten percent of P. aeruginosa isolates were MDR, associated with prior exposure to antipseudomonal antibiotics (P = .002), with amikacin and colistin remaining the most effective antimicrobials. Novel antimicrobials targeting MDR Gram-negative organisms were also examined, and 100% of the MDR P. aeruginosa isolates were resistant to imipenem/relabactam, while ceftazidime/avibactam and ceftolozane/tazobactam were active against 35% and 56% of the isolates, respectively. We identified two previously unrecognized P. aeruginosa outbreaks involving 13 patients., Conclusions: Pseudomonas aeruginosa continues to be a major cause of morbidity, affecting severely injured combat casualties, with emergent antimicrobial resistance upon serial isolation. Among MDR P. aeruginosa, active antimicrobials remain the oldest and most toxic. Despite ongoing efforts, outbreaks are still noted, reinforcing the crucial role of antimicrobial stewardship and infection control., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The Deployment and Travel Medicine Knowledge, Attitude, Practice and Outcomes Study investigates the various clinician and traveler contributions to medical outcomes within the U.S. Military Health System. Travelers' diarrhea is among the most common travel-related illnesses, making travelers' diarrhea self-treatment (TDST) important for traveler health. A cohort of 80,214 adult travelers receiving malaria chemoprophylaxis for less than 6 weeks of travel were identified within the U.S. Department of Defense Military Health System Data Repository. Associated prescriptions for TDST medications within 2 weeks of chemoprophylaxis prescriptions were identified. Prescription patterns were compared by service member versus beneficiary status and site of care, military facility versus civilian facility. At military facilities, medical provider demographics were analyzed by clinical specialty and categorized as travel medicine specialists versus nonspecialists. Overall, there was low prescribing of TDST, particularly among civilian providers and military nonspecialists, despite guidelines recommending self-treatment of moderate to severe travelers' diarrhea. This practice gap was largest among service member travelers, but also existed for beneficiaries. Compared with nonspecialists, military travel medicine specialists were more likely to prescribe a combination of an antibiotic and antimotility agent to beneficiaries, more likely to provide any form of TDST to service members, and more likely to prescribe azithromycin than quinolones when using antibiotics. Our study suggests that enhancing provider knowledge and use of travelers' diarrhea treatment recommendations combined with improved access to formal travel medicine services may be important to increase the quality of care.

Background: The frequency of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is unclear and may be influenced by how symptoms are evaluated. In this study, we sought to determine the frequency of asymptomatic SARS-CoV-2 infections in a prospective cohort of health care workers (HCWs)., Methods: A prospective cohort of HCWs, confirmed negative for SARS-CoV-2 exposure upon enrollment, were evaluated for SARS-CoV-2 infection by monthly analysis of SARS-CoV-2 antibodies as well as referral for polymerase chain reaction testing whenever they exhibited symptoms of coronavirus disease 2019 (COVID-19). Participants completed the standardized and validated FLU-PRO Plus symptom questionnaire scoring viral respiratory disease symptom intensity and frequency at least twice monthly during baseline periods of health and each day they had any symptoms that were different from their baseline., Results: Two hundred sixty-three participants were enrolled between August 25 and December 31, 2020. Through February 28, 2021, 12 participants were diagnosed with SARS-CoV-2 infection. Symptom analysis demonstrated that all 12 had at least mild symptoms of COVID-19, compared with baseline health, near or at time of infection., Conclusions: These results suggest that asymptomatic SARS-CoV-2 infection in unvaccinated, immunocompetent adults is less common than previously reported. While infectious inoculum doses and patient factors may have played a role in the clinical manifestations of SARS-CoV-2 infections in this cohort, we suspect that the high rate of symptomatic disease was due primarily to participant attentiveness to symptoms and collection of symptoms in a standardized, prospective fashion. These results have implications for studies that estimate SARS-CoV-2 infection prevalence and for public health measures to control the spread of this virus., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: We assessed the compliance with self-collection of stool smears on Whatman® FTA® Elute Card (FTA Card) and detection of travellers' diarrhoea (TD)-associated pathogens by using a quantitative Polymerase Chain Reaction (PCR) assay [customized TaqMan® array card (TAC)] in a prospective, observational cohort of travellers., Methods: Enrolled travellers documented symptoms on a travel diary and collected an FTA Card during a diarrhoeal episode, or at the end of travel if they remained asymptomatic. TAC testing was performed on FTA Cards from TD cases and 1:1 matched asymptomatic controls and 1:1 matched loose stool cases that did not meet TD criteria. Odds ratios were used to determine the association between detected pathogens and TD., Results: Of 2456 travellers, 484 (19.7%) completed an illness diary and met TD criteria, and 257 (53.1%) collected an FTA Card during the TD episode. FTA Cards were stored for a median of 2 years at room temperature (IQR: 1-4 years) before extraction and testing. The overall TAC detection rate in TD cases was 58.8% (95% CI: 52.5-64.8). Enterotoxigenic Escherichia coli was the most common pathogen in TD cases (26.8%), and 3.5% of samples were positive for norovirus. The odds of detecting TD-associated pathogens in 231 matched cases and asymptomatic controls were 5.4 (95% CI: 3.6-8.1) and 2.0 (95% CI: 1.1-3.7) in 121 matched TD and loose stool cases (P < 0.05). Enteroaggregative E. coli was the most common pathogen detected in asymptomatic controls and loose stool cases. Detection of diarrhoeagenic E. coli, Shigella/enteroinvasive E. coli and Campylobacter spp. was significantly associated with TD., Conclusion: FTA Cards are a useful adjunct to traditional stool collection methods for evaluating the pathogen-specific epidemiology of TD in austere environments. Qualitative detection of pathogens was associated with TD. Measures to improve compliance and quality of FTA Card collection with decreased storage duration may further optimize detection., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Travellers' diarrhoea (TD) is the most common travel-related illness with an estimated 10 million people afflicted annually. Outcome measures to assess the efficacy of primary and secondary TD interventions were historically based on diarrhoea frequency with ≥1 associated gastrointestinal symptom. Furthermore, efficacy determination is often made on the presence or absence of TD, rather than on TD illness severity. Current severity classifications are based on subjective consideration of impact of illness on activity. We sought to develop a standardized scoring system to characterize TD severity to potentially apply as a secondary outcome in future field studies., Methods: Data on multiple signs and symptoms were obtained from a previously published multisite TD treatment trial conducted by the US Department of Defense (TrEAT TD). Correlation, regression and multiple correspondence analyses were performed to assess impact on activity and a TD severity score was established., Results: Numerous signs and symptoms were associated with impaired function, with malaise and nausea most strongly associated [odds ratio (OR) 5.9-44.3, P < 0.0001 and OR 2.8-37.1, P < 0.0001, respectively). Based on co-varying symptomatology, a TD severity score accounting for diarrhoea frequency in addition to several signs and symptoms was a better predictor of negative impact on function than any single sign/symptom (X2 = 127.16, P < 0.001). Additionally, there was a significant difference (P < 0.0001) in the mean TD severity score between those with acute watery diarrhoea (3.9 ± 1.9) and those with dysentery or acute febrile illness (6.2 ± 2.0)., Conclusions: The newly developed disease severity score better predicted a negative impact on activity due to TD than did any single sign or symptom. Incorporating multiple parameters into the TD severity score better captures illness severity and moves the field towards current recommendations for TD management by considering symptoms with high functional impact. Further validation of this score is needed in non-military travellers and other settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Background: Nasopharyngeal (NP) swabs are the standard for SARS-CoV-2 diagnosis. If less invasive alternatives to NP swabs (eg, oropharyngeal [OP] or nasal swabs [NS]) are comparably sensitive, the use of these techniques may be preferable in terms of comfort, convenience, and safety., Methods: This study compared the detection of SARS-CoV-2 in swab samples collected on the same day among participants with at least one positive PCR test., Results: Overall, 755 participants had at least one set of paired swabs. Concordance between NP and other swab types was 75% (NS), 72% (OP), 54% (rectal swabs [RS]), and 78% (NS/OP combined). Kappa values were moderate for the NS, OP, and NS/OP comparisons (0.50, 0.45, and 0.54, respectively). Highest sensitivity relative to NP (0.87) was observed with a combination of NS/OP tests (positive if either NS or OP was positive). Sensitivity of the non-NP swab types was highest in the first week postsymptom onset and decreased thereafter. Similarly, virus RNA quantity was highest in the NP swabs as compared with NS, OP, and RS within two weeks postsymptom onset. OP and NS performance decreased as virus RNA quantity decreased. No differences were noted between NS specimens collected at home or in clinic., Conclusions: NP swabs detected more SARS-CoV-2 cases than non-NP swabs, and the sensitivity of the non-NP swabs decreased with time postsymptom onset. While other swabs may be simpler to collect, NP swabs present the best chance of detecting SARS-CoV-2 RNA, which is essential for clinical care as well as genomic surveillance., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2021.)

Background: The relationship between postvaccination symptoms and strength of antibody responses is unclear. The goal of this study was to determine whether adverse effects caused by vaccination with the Pfizer/BioNTech BNT162b2 vaccine are associated with the magnitude of vaccine-induced antibody levels., Methods: We conducted a single-center, observational cohort study consisting of generally healthy adult participants that were not severely immunocompromised, had no history of coronavirus disease 2019, and were seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein before vaccination. Severity of vaccine-associated symptoms was obtained through participant-completed questionnaires. Testing for immunoglobulin G antibodies against SARS-CoV-2 spike protein and receptor-binding domain was conducted using microsphere-based multiplex immunoassays performed on serum samples collected at monthly visits. Neutralizing antibody titers were determined by microneutralization assays., Results: Two hundred six participants were evaluated (69.4% female, median age 41.5 years old). We found no correlation between vaccine-associated symptom severity scores and vaccine-induced antibody titers 1 month after vaccination. We also observed that (1) postvaccination symptoms were inversely correlated with age and weight and more common in women, (2) systemic symptoms were more frequent after the second vaccination, (3) high symptom scores after first vaccination were predictive of high symptom scores after second vaccination, and (4) older age was associated with lower titers., Conclusions: Lack of postvaccination symptoms after receipt of the BNT162b2 vaccine does not equate to lack of vaccine-induced antibodies 1 month after vaccination., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2021.)

Background: We evaluated clinical outcomes, functional burden, and complications 1 month after coronavirus disease 2019 (COVID-19) infection in a prospective US Military Health System (MHS) cohort of active duty, retiree, and dependent populations using serial patient-reported outcome surveys and electronic medical record (EMR) review., Methods: MHS beneficiaries presenting at 9 sites across the United States with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, a COVID-19-like illness, or a high-risk SARS-CoV-2 exposure were eligible for enrollment. Medical history and clinical outcomes were collected through structured interviews and International Classification of Diseases-based EMR review. Risk factors associated with hospitalization were determined by multivariate logistic regression., Results: A total of 1202 participants were enrolled. There were 1070 laboratory-confirmed SARS-CoV-2 cases and 132 SARS-CoV-2-negative participants. In the first month post-symptom onset among the SARS-CoV-2-positive cases, there were 212 hospitalizations, 80% requiring oxygen, 20 ICU admissions, and 10 deaths. Risk factors for COVID-19-associated hospitalization included race (increased for Asian, Black, and Hispanic compared with non-Hispanic White), age (age 45-64 and 65+ compared with <45), and obesity (BMI≥30 compared with BMI<30). Over 2% of survey respondents reported the need for supplemental oxygen, and 31% had not returned to normal daily activities at 1 month post-symptom onset., Conclusions: Older age, reporting Asian, Black, or Hispanic race/ethnicity, and obesity are associated with SARS-CoV-2 hospitalization. A proportion of acute SARS-CoV-2 infections require long-term oxygen therapy; the impact of SARS-CoV-2 infection on short-term functional status was substantial. A significant number of MHS beneficiaries had not yet returned to normal activities by 1 month., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The inFLUenza Patient-Reported Outcome Plus (FLU-PRO Plus) is a patient-reported outcome data collection instrument assessing symptoms of viral respiratory tract infections across 8 body systems. This study evaluated the measurement properties of FLU-PRO Plus in a study enrolling individuals with coronavirus disease 2019 (COVID-19)., Methods: Data from a prospective cohort study (EPICC) in US Military Health System beneficiaries evaluated for COVID-19 was utilized. Adults with symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with FLU-PRO Plus survey information within 1 week of symptom onset were included. Reliability of FLU-PRO Plus was estimated using intraclass correlation coefficient (ICC; 2 days' reproducibility). Known-groups validity was assessed using patient global assessment (PGA) of disease severity. Patient report of return to usual health was used to assess responsiveness (day 1-6/7)., Results: Two hundred twenty-six SARS-CoV-2-positive participants were included in the analysis. Reliability among those who reported no change in their symptoms from one day to the next was high for most domains (ICC range, 0.68-0.94 for day 1 to day 2). Construct validity was demonstrated by moderate to high correlation between the PGA rating of disease severity and domain and total scores (eg, total scores correlation: 0.69 [influenza-like illness severity], 0.69 [interference in daily activities], and -0.58 [physical health]). In addition, FLU-PRO Plus demonstrated good known-groups validity, with increasing domain and total scores observed with increasing severity ratings., Conclusions: FLU-PRO Plus performs well in measuring signs and symptoms in SARS-CoV-2 infection with excellent construct validity, known-groups validity, and responsiveness to change. Standardized data collection instruments facilitate meta-analyses, vaccine effectiveness studies, and other COVID-19 research activities., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2021.)