Changes in the Seroprevalence of Tick-Borne Rickettsia and Ehrlichia Among Soldiers-Fort Liberty, North Carolina, 1991-2019.

We obtained samples from the Department of Defense Serum Repository from soldiers who were stationed at Fort Liberty, North Carolina, between 1991 and 2019 to assess temporal trends in tick-borne rickettsiosis and ehrlichiosis. Serological evidence of infection was common, with nearly 1 in 5 (18.9%) demonstrating antibodies. We observed significant decreases in Rickettsia seroprevalence (adjusted odds ratio [aOR], 0.42 [95% CI, .27-.65], P = .0001) while over the same period Ehrlichia seroprevalence, albeit less common, nearly doubled (aOR, 3.61 [95% CI, 1.10-13.99], P = .048). The increase in Ehrlichia seroprevalence likely reflects increased transmission resulting from the expanding geographic range of the lone star tick.

Understanding "Hybrid Immunity": Comparison and Predictors of Humoral Immune Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) Vaccines.

BACKGROUND: Comparison of humoral responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinees, those with SARS-CoV-2 infection, or combinations of vaccine/ infection ("hybrid immunity") may clarify predictors of vaccine immunogenicity. METHODS: We studied 2660 US Military Health System beneficiaries with a history of SARS-CoV-2 infection-alone (n = 705), vaccination-alone (n = 932), vaccine-after-infection (n = 869), and vaccine-breakthrough-infection (n = 154). Peak anti-spike-immunoglobulin G (IgG) responses through 183 days were compared, with adjustment for vaccine product, demography, and comorbidities. We excluded those with evidence of clinical or subclinical SARS-CoV-2 reinfection from all groups. RESULTS: Multivariable regression results indicated that vaccine-after-infection anti-spike-IgG responses were higher than infection-alone (P < .01), regardless of prior infection severity. An increased time between infection and vaccination was associated with greater post-vaccination IgG response (P < .01). Vaccination-alone elicited a greater IgG response but more rapid waning of IgG (P < .01) compared with infection-alone (P < .01). BNT162b2 and mRNA-1273 vaccine-receipt was associated with greater IgG responses compared with JNJ-78436735 vaccine-receipt (P < .01), regardless of infection history. Those with vaccine-after-infection or vaccine-breakthrough-infection had a more durable anti-spike-IgG response compared to infection-alone (P < .01). CONCLUSIONS: Vaccine-receipt elicited higher anti-spike-IgG responses than infection-alone, although IgG levels waned faster in those vaccinated (compared to infection-alone). Vaccine-after-infection elicits a greater humoral response compared with vaccine or infection alone; and the timing, but not disease severity, of prior infection predicted these post-vaccination IgG responses. While differences between groups were small in magnitude, these results offer insights into vaccine immunogenicity variations that may help inform vaccination timing strategies.

SARS-CoV-2 infection is associated with self-reported post-acute neuropsychological symptoms within six months of follow-up.

BACKGROUND: Chronic neuropsychological sequelae following SARS-CoV-2 infection, including depression, anxiety, fatigue, and general cognitive difficulties, are a major public health concern. Given the potential impact of long-term neuropsychological impairment, it is important to characterize the frequency and predictors of this post-infection phenotype. METHODS: The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal study assessing the impact of SARS-CoV-2 infection in U.S. Military Healthcare System (MHS) beneficiaries, i.e. those eligible for care in the MHS including active duty servicemembers, dependents, and retirees. Four broad areas of neuropsychological symptoms were assessed cross-sectionally among subjects 1-6 months post-infection/enrollment, including: depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), fatigue (PROMIS® Fatigue 7a), and cognitive function (PROMIS® Cognitive Function 8a and PROMIS® Cognitive Function abilities 8a). Multivariable Poisson regression models compared participants with and without SARS-CoV-2 infection history on these measures, adjusting for sex, ethnicity, active-duty status, age, and months post-first positive or enrollment of questionnaire completion (MPFP/E); models for fatigue and cognitive function were also adjusted for depression and anxiety scores. RESULTS: The study population included 2383 participants who completed all five instruments within six MPFP/E, of whom 687 (28.8%) had at least one positive SARS-CoV-2 test. Compared to those who had never tested positive for SARS-CoV-2, the positive group was more likely to meet instrument-based criteria for depression (15.4% vs 10.3%, p<0.001), fatigue (20.1% vs 8.0%, p<0.001), impaired cognitive function (15.7% vs 8.6%, p<0.001), and impaired cognitive function abilities (24.3% vs 16.3%, p<0.001). In multivariable models, SARS-CoV-2 positive participants, assessed at an average of 2.7 months after infection, had increased risk of moderate to severe depression (RR: 1.44, 95% CI 1.12-1.84), fatigue (RR: 2.07, 95% CI 1.62-2.65), impaired cognitive function (RR: 1.64, 95% CI 1.27-2.11), and impaired cognitive function abilities (RR: 1.41, 95% CI 1.15-1.71); MPFP/E was not significant. CONCLUSIONS: Participants with a history of SARS-CoV-2 infection were up to twice as likely to report cognitive impairment and fatigue as the group without prior SARS-CoV-2 infection. These findings underscore the continued importance of preventing SARS-CoV-2 infection and while time since infection/enrollment was not significant through 6 months of follow-up, this highlights the need for additional research into the long-term impacts of COVID-19 to mitigate and reverse these neuropsychological outcomes.

Exposomic Signatures of Cervical Pain.

INTRODUCTION: We evaluated risk factors associated with cervical pain (CP) among officers and enlisted members of the U.S. Army and Marine Aviation community using an exposomic approach. Specifically, we aimed to determine the factors associated with reported CP. MATERIALS AND METHODS: This is a retrospective cohort study that utilized the Medical Assessment and Readiness System housed at Womack Army Medical Center to evaluate the longitudinal data taken from medical and workforce resources. This study included 77,864 active duty AMAC members during October 2015-December 2019. Multivariable mixed-effects logistic regression was used to assess the relationship between the independent variables of rank, service time, deployment, Armed Forces Qualification Test score, tobacco use, alcohol use, age, gender, race, ethnicity, body mass index, marital status, and education level and the dependent variable, incidence occurrence of CP. RESULTS: The total analysis included 77,864 individuals with 218,180 person-years of observations. The incidence rate of CP was 18.8 per 100 person-years, with a 12% period prevalence. Cervical pain was independently associated with rank, service time, Armed Forces Qualification Test score, and alcohol use (all P < .05). CONCLUSIONS: Our longitudinal exposomic signatures-based approach aims to complement the outcomes of data science and analytics from Medical Assessment and Readiness System with validations of objective biochemical indicator species observed in Army and Marine Aviation community members suffering from CP. This initial approach using parallel track complementarity has the potential of substantiating the underlying mechanisms foundational to design prospective personalized algorithms that can be used as a predictive model. Finally, a specific evaluation of occupational risk factors may provide insight into factors not readily ascertained from the civilian literature.

Exposomic Signatures of Tinnitus and/or Hearing Loss.

INTRODUCTION: We evaluated the risk factors associated with tinnitus and/or hearing loss (THL) among active duty (AD) members of the U.S. Army and Marine Aviation Community (AMAC) using an exposomic approach. Specifically, we aimed to determine the factors associated with the reported THL in the Military Health System. METHODS: Longitudinal data were obtained from the Medical Assessment and Readiness System housed at Womack Army Medical Center, Fort Bragg, NC, for a retrospective cohort study that included 78,546 AD AMAC members from October 2015 to December 2019. Multivariable mixed-effects logistic regression was used to assess the relationship between THL and numerous variables to include rank, service time, deployment, tobacco use, alcohol use, age, gender, race, ethnicity, and body mass index. RESULTS: Our analysis included a total of 220,044 person-years of observations. The THL incidence rate was 6.7 per 100 person-years, with an 8.1% period prevalence. THL was associated with age, gender, body mass index, race, deployment, service time, marital status, and tobacco use (all P < .05). Service time greater than 16 years had the greatest odds ratio of THL (4.46, 95% CI: 3.58-5.55, P < .001). CONCLUSIONS: Our assessment shows the utility of using an exposomic approach to create member-specific personalized clinical algorithms for health outcomes. We examined individuals with THL diagnoses and identified a combination of risk factors from biomedical, lifestyle, environmental, and stochastic sources. Taken together, the risk factors identified across the four exposomic domains could help understand the etiology of THL. Our exposomic methodology could be the foundation for generating predictive models. Finally, a specific evaluation of occupational risk factors may provide insight into aspects not readily available from civilian literature. In upcoming years, as the Medical Assessment and Readiness System matures, we will expand our analyses to include prospective, untargeted metabolites and biomarker data.

A machine learning approach identifies distinct early-symptom cluster phenotypes which correlate with hospitalization, failure to return to activities, and prolonged COVID-19 symptoms.

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.

Decreased Self-reported Physical Fitness Following SARS-CoV-2 Infection and the Impact of Vaccine Boosters in a Cohort Study.

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.

Health coaching and genetic risk testing in primary care: Randomized controlled trial.

OBJECTIVE: Accessible interventions are needed to prevent coronary heart disease (CHD) and Type 2 diabetes (T2D). This prospective, randomized, controlled trial evaluated remote health coaching (HC), genetic risk testing (GRT), or both added to standardized risk assessment (SRA) in at-risk military primary care patients. METHOD: Using a 2 × 2 factorial longitudinal design, 200 Air Force at-risk participants provided primary outcomes at baseline, 3-, 6- (HC endpoint), and 12-months. Secondary measures were taken less often. Per protocol analyses used linear models and logistic regression; intent-to-treat (ITT) analyses used mixed models. RESULTS: Compared with those not receiving HC, the HC group was 3.6 times more likely to report moderate to intense physical activity at 6-months (p = .0009), and 2.9 times more likely to report such at 12-months (p = .0065). ITT longitudinal model did not reach significance (p = .0885). The HC group reported lower emotional representations of illness at 6-weeks and lower depression at 6 months. There were no other significant findings. HC and GRT interacted; higher T2D risk participants receiving HC were 4.7 times more likely to report higher stage of change for exercise at 6-months, and lost 2.2 kg more by 12-months. Lower T2D risk participants receiving HC perceived greater control over CHD risk at 6-weeks, and averaged lower 6-month depression. CONCLUSIONS: Remote HC after SRA increased physical activity, which was sustained 6-months later. Incorporating GRT into SRA warrants further exploration regarding the potential to leverage HC for weight loss in elevated T2D risk participants, and for depression in lower T2D risk participants. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

COVID-19 Patient-Reported Symptoms Using FLU-PRO Plus in a Cohort Study: Associations With Infecting Genotype, Vaccine History, and Return to Health.

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 epidemiology, immunology, and clinical characteristics 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 (ß = -0.39; 95% CI, -0.57 to -0.21). The Delta variant was associated with higher total scores (ß = 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.

An Analysis of SARS-CoV-2 Vaccine Reactogenicity: Variation by Type, Dose, and History, Severity, and Recency of Prior SARS-CoV-2 Infection.

Background: There is limited information on the functional consequences of coronavirus disease 2019 (COVID-19) vaccine side effects. To support patient counseling and public health messaging, we describe the risk and correlates of COVID-19 vaccine side effects sufficient to prevent work or usual activities and/or lead to medical care ("severe" side effects). Methods: The EPICC study is a longitudinal cohort study of Military Healthcare System beneficiaries including active duty service members, dependents, and retirees. We studied 2789 adults who were vaccinated between December 2020 and December 2021. Results: Severe side effects were most common with the Ad26.COV2.S (Janssen/Johnson and Johnson) vaccine, followed by mRNA-1273 (Moderna) then BNT162b2 (Pfizer/BioNTech). Severe side effects were more common after the second than first dose (11% vs 4%; P < .001). First (but not second) dose side effects were more common in those with vs without prior severe acute respiratory syndrome coronavirus 2 infection (9% vs 2%; adjusted odds ratio [aOR], 5.84; 95% CI, 3.8-9.1), particularly if the prior illness was severe or critical (13% vs 2%; aOR, 10.57; 95% CI, 5.5-20.1) or resulted in inpatient care (17% vs 2%; aOR, 19.3; 95% CI, 5.1-72.5). Side effects were more common in women than men but not otherwise related to demographic factors. Conclusions: Vaccine side effects sufficient to prevent usual activities were more common after the second than first dose and varied by vaccine type. First dose side effects were more likely in those with a history of COVID-19-particularly if that prior illness was severe or associated with inpatient care. These findings may assist clinicians and patients by providing a real-world evaluation of the likelihood of experiencing impactful postvaccine symptoms.

Evidence that Sp1 positively and Sp3 negatively regulate and androgen does not directly regulate functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) gene expression in normal human prostate epithelial cells.

In this project, we studied the gene regulation of 15-lipoxygenase 2 (15-LOX2), the most abundant arachidonate-metabolizing LOX in adult human prostate and a negative cell-cycle regulator in normal human prostate (NHP) epithelial cells. Through detailed in silico promoter examination and promoter deletion and activity analysis, we found that several Sp1 sites (i.e., three GC boxes and one CACCC box) in the proximal promoter region play a critical role in regulating 15-LOX2 expression in NHP cells. Several pieces of evidence further suggest that the Sp1 and Sp3 proteins play a physiologically important role in positively and negatively regulating the 15-LOX2 gene expression, respectively. First, mutations in the GC boxes affected the 15-LOX2 promoter activity. Second, both Sp1 and Sp3 proteins were detected in the protein complexes that bound the GC boxes revealed by electrophoretic mobility shift assay. Third, importantly, inhibition of Sp1 activity or overexpression of Sp3 both inhibited the endogenous 15-LOX2 mRNA expression. Since 15-LOX2 is normally expressed in the prostate luminal epithelial cells, we subsequently explored whether androgen/androgen receptor may directly regulate its gene expression. The results indicate that androgen does not directly regulate 15-LOX2 gene expression. Together, these observations provide insight on how 15-LOX2 gene expression may be regulated in NHP cells.

Efficacy of medical grade honey against multidrug-resistant organisms of operational significance: part I.

BACKGROUND: MEDIHONEY (Derma Sciences, Inc., Toronto, Ontario M1S 3S4, Canada) was cleared by the Food and Drug Administration for use on tramatic wounds, diabetic ulcers, and second-degree burns against normal skin flora but not necessarily against multidrug-resistant organisms (MDROs) infecting these wounds or its associated recovery and healing rate. METHODS: Here, we report on the efficacy of this medical grade honey treatment against two MDROs (Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus [MRSA]). In this initial phase (Part I), an in-laboratory validation and characterization of the efficacy against antibiotic-resistant bacteria were performed in vitro. RESULTS: The antimicrobial resistance of both MDROs was confirmed in vitro using standard microbiology techniques and species' DNA signatures. The minimum inhibitory concentration of the MEDIHONEY was determined to be 3.5% for MRSA and 8.5% for A. baumannii. The minimum bactericidal concentrations determined against MRSA and multidrug-resistant A. baumannii were shown to be 9.5% and 10.5%, respectively. CONCLUSION: Our in vitro findings support the efficacy of MEDIHONEY against MRSA and A. baumannii as requested by first responders. We also conducted screening assays using other "supermarket brands" of honey. All cultures from the latter showed bacterial and fungal growths. The use of supermarket brand honey for wound treatment is discouraged.

Subcellular localization and tumor-suppressive functions of 15-lipoxygenase 2 (15-LOX2) and its splice variants.

15-Lipoxygenase 2 (15-LOX2), the most abundant arachidonate (AA)-metabolizing enzyme expressed in adult human prostate, is a negative cell-cycle regulator in normal human prostate epithelial cells. Here we study the subcellular distribution of 15-LOX2 and report its tumor-suppressive functions. Immunocytochemistry and biochemical fractionation reveal that 15-LOX2 is expressed at multiple subcellular locations, including cytoplasm, cytoskeleton, cell-cell border, and nucleus. Surprisingly, the three splice variants of 15-LOX2 we previously cloned, i.e. 15-LOX2sv-a/b/c, are mostly excluded from the nucleus. A potential bi-partite nuclear localization signal (NLS),203RKGLWRSLNEMKRIFNFRR221, is identified in the N terminus of 15-LOX2, which is retained in all splice variants. Site-directed mutagenesis reveals that this putative NLS is only partially involved in the nuclear import of 15-LOX2. To elucidate the relationship between nuclear localization, enzymatic activity, and tumor suppressive functions, we established PCa cell clones stably expressing 15-LOX2 or 15-LOX2sv-b. The 15-LOX2 clones express 15-LOX2 in the nuclei and possess robust enzymatic activity, whereas 15-LOX2sv-b clones show neither nuclear protein localization nor AA-metabolizing activity. To our surprise, both 15-LOX2- and 15-LOX2sv-b-stable clones proliferate much slower in vitro when compared with control clones. More importantly, when orthotopically implanted in nude mouse prostate, both 15-LOX2 and 15-LOX2sv-b suppress PC3 tumor growth in vivo. Together, these results suggest that both 15-LOX2 and 15-LOX2sv-b suppress prostate tumor development, and the tumor-suppressive functions apparently do not necessarily depend on AA-metabolizing activity and nuclear localization.

Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells.

15-Lipoxygenase 2 (15-LOX2) is a recently cloned human lipoxygenase that shows tissue-restricted expression in prostate, lung, skin, and cornea. The protein level and enzymatic activity of 15-LOX2 have been shown to be down-regulated in prostate cancers compared with normal and benign prostate tissues. The biological function of 15-LOX2 and the role of loss of 15-LOX2 expression in prostate tumorigenesis, however, remain unknown. We report the cloning and functional characterization of 15-LOX2 and its three splice variants (termed 15-LOX2sv-a, 15-LOX2sv-b, and 15-LOX2sv-c) from primary prostate epithelial cells. Western blotting with multiple primary prostate cell strains and prostate cancer cell lines reveals that the expression of 15-LOX2 is lost in all prostate cancer cell lines, accompanied by decreased enzymatic activity revealed by liquid chromatography/tandem mass spectrometry analyses. Further experiments show that the loss of 15-LOX2 expression results from transcriptional repression caused by mechanism(s) other than promoter hypermethylation or histone deacetylation. Subsequent functional studies indicate the following: 1) the 15-LOX2 product, 15(S)-hydroxyeicosatetraenoic acid, inhibits prostate cancer cell cycle progression; 2) 15-LOX2 expression in primary prostate epithelial cells is inversely correlated with cell cycle; and 3) restoration of 15-LOX2 expression in prostate cancer cells partially inhibits cell cycle progression. Taken together, these results suggest that 15-LOX2 could be a suppressor of prostate cancer development, which functions by restricting cell cycle progression.