Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 54 Records) |
Query Trace: Harmon J [original query] |
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Non-persistent endocrine disrupting chemical mixtures and uterine leiomyomata in the Study of Environment, Lifestyle and Fibroids (SELF)
Fruh V , Wesselink AK , Schildroth S , Bethea TN , Geller RJ , Calafat AM , Coull BA , Wegienka G , Harmon QE , Baird DD , Wise LA , Henn BC . Chemosphere 2024 142050 BACKGROUND: Results of studies investigating associations between individual endocrine-disrupting chemicals (EDCs) and incidence of uterine leiomyomata (UL), a hormone-dependent gynecological condition, have been inconsistent. However, few studies have evaluated simultaneous exposure to a mixture of EDCs with UL incidence. METHODS: We conducted a case-cohort analysis (n=708) of data from the Study of the Environment, Lifestyle and Fibroids (SELF), a prospective cohort study. Participants were aged 23-35 years at enrollment, had an intact uterus, and identified as Black or African American. We measured biomarker concentrations of 21 non-persistent EDCs, including phthalates, phenols, parabens, and triclocarban, in urine collected at baseline, 20-month, and 40-month clinic visits. We ascertained UL incidence and characteristics using ultrasounds at baseline and approximately every 20 months through 60 months. We used probit Bayesian Kernel Machine Regression (BKMR-P) to evaluate joint associations between EDC mixtures with cumulative UL incidence. We estimated the mean difference in the probit of UL incidence over the study period, adjusting for baseline age, education, years since last birth, parity, smoking status and body mass index. We converted probit estimates to odds ratios for ease of interpretation. RESULTS: We observed that urinary concentrations of the overall EDC mixture were inversely associated with UL incidence in the overall mixtures model, with the strongest inverse associations at the 70(th) percentile of all biomarkers compared with their 50(th) percentile (odds ratio =0.59; 95% confidence interval: 0.36, 0.96). Strongest contributors to the joint association for the mixture were bisphenol S (BPS), ethyl paraben (EPB), bisphenol F (BPF) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), which each demonstrated inverse associations except for MECPP. There was suggestive evidence of an interaction between MECPP and EPB. CONCLUSION: In this prospective ultrasound study, we observed evidence of an inverse association between the overall mixture of urinary biomarker concentrations of non-persistent EDCs with UL incidence. |
Molecular Analysis of Influenza A(H3N2) and A(H1N1)pdm09 Viruses circulating in the Democratic Republic of Congo, 2014.
Nkwembe E , Cintron R , Sessions W , Kavunga H , Babakazo P , Manya L , Muyembe JJ . J Harmon Res Med Health Sci 2016 3 (4) 247-264 BACKGROUND: Very little is known about influenza viruses circulating in the Democratic Republic of Congo (DRC). We aim to characterize genetically and antigenically Influenza A(H3N2) and A(H1N1)pdm09 viruses circulating in the country. METHODS: From August to December 2014, specimens were collected from patients with influenza like-illness (ILI) or severe acute respiratory infection (SARI) in various surveillance sites. Specimens were tested using real time reverse transcription polymerase chain reaction (RT-PCR) method for the detection of influenza viruses. Positive influenza samples with a cycle threshold (Ct) <30 were genetically and antigenically characterized. RESULTS: 32 samples tested were found positive to influenza A with Ct <30. At CDC Atlanta, 28 out of 32 samples (88%) were tested positive for influenza A virus, including 26 seasonal influenza A viruses subtype H3N2 and 2 pandemic influenza A viruses subtype H1N1pdm 2009. The majority of influenza A(H3N2) viruses were antigenically related to the A/Switzerland/9715293/2013 vaccine virus, while two influenza A(H1N1)pdm09 isolates were antigenically characterized as A/California/07/2009-like. All A(H3N2) and A(H1N1)pdm09 virus isolates characterized were sensitive to oseltamivir and zanamivir. CONCLUSION: Two genetically distinct influenza subtypes were co-circulating in the DRCongo. Effective measures against influenza have been suggested. |
Peripheral immune responses to filoviruses in a reservoir versus spillover hosts reveal transcriptional correlates of disease
Guito JC , Arnold CE , Schuh AJ , Amman BR , Sealy TK , Spengler JR , Harmon JR , Coleman-McCray JD , Sanchez-Lockhart M , Palacios GF , Towner JS , Prescott JB . Front Immunol 2023 14 1306501 Several filoviruses, including Marburg virus (MARV), cause severe disease in humans and nonhuman primates (NHPs). However, the Egyptian rousette bat (ERB, Rousettus aegyptiacus), the only known MARV reservoir, shows no overt illness upon natural or experimental infection, which, like other bat hosts of zoonoses, is due to well-adapted, likely species-specific immune features. Despite advances in understanding reservoir immune responses to filoviruses, ERB peripheral blood responses to MARV and how they compare to those of diseased filovirus-infected spillover hosts remain ill-defined. We thus conducted a longitudinal analysis of ERB blood gene responses during acute MARV infection. These data were then contrasted with a compilation of published primate blood response studies to elucidate gene correlates of filovirus protection versus disease. Our work expands on previous findings in MARV-infected ERBs by supporting both host resistance and disease tolerance mechanisms, offers insight into the peripheral immunocellular repertoire during infection, and provides the most direct known cross-examination between reservoir and spillover hosts of the most prevalently-regulated response genes, pathways and activities associated with differences in filovirus pathogenesis and pathogenicity. |
Characterization of humoral responses to Nipah virus infection in the Syrian Hamster model of disease
Scholte FEM , Rodriguez SE , Welch SR , Davies KA , Genzer SC , Coleman-McCray JD , Harmon JR , Sorvillo TE , Lo MK , Karaaslan E , Bergeron E , Montgomery JM , Spengler JR , Spiropoulou CF . J Infect Dis 2023 Nipah virus (NiV) is a highly pathogenic paramyxovirus. The Syrian hamster model recapitulates key features of human NiV disease and is a critical tool for evaluating antivirals and vaccines. Here we describe longitudinal humoral immune responses in NiV-infected Syrian hamsters. Samples were obtained 1-28 days after infection and analyzed by ELISA, neutralization, and Fc-mediated effector function assays. NiV infection elicited robust antibody responses against the nucleoprotein and attachment glycoprotein. Levels of neutralizing antibodies were modest and only detectable in surviving animals. Fc-mediated effector functions were mostly observed in nucleoprotein-targeting antibodies. Antibody levels and activities positively correlated with challenge dose. |
Recombinant Sudan virus and evaluation of humoral cross-reactivity between Ebola and Sudan virus glycoproteins after infection or rVSV-ΔG-ZEBOV-GP vaccination
Kainulainen MH , Harmon JR , Whitesell AN , Bergeron E , Karaaslan E , Cossaboom CM , Malenfant JH , Kofman A , Montgomery JM , Choi MJ , Albariño CG , Spiropoulou CF . Emerg Microbes Infect 2023 12 (2) 2265660 Ebola disease outbreaks are major public health events because of human-to-human transmission and high mortality. These outbreaks are most often caused by Ebola virus, but at least three related viruses can also cause the disease. In 2022, Sudan virus re-emerged causing more than 160 confirmed and probable cases. This report describes generation of a recombinant Sudan virus and demonstrates its utility by quantifying antibody cross-reactivity between Ebola and Sudan virus glycoproteins after human infection or vaccination with a licensed Ebola virus vaccine. |
Single-dose mucosal replicon-particle vaccine protects against lethal Nipah virus infection up to 3 days after vaccination
Welch SR , Spengler JR , Genzer SC , Coleman-McCray JD , Harmon JR , Sorvillo TE , Scholte FEM , Rodriguez SE , O'Neal TJ , Ritter JM , Ficarra G , Davies KA , Kainulainen MH , Karaaslan E , Bergeron É , Goldsmith CS , Lo MK , Nichol ST , Montgomery JM , Spiropoulou CF . Sci Adv 2023 9 (31) eadh4057 Nipah virus (NiV) causes a highly lethal disease in humans who present with acute respiratory or neurological signs. No vaccines against NiV have been approved to date. Here, we report on the clinical impact of a novel NiV-derived nonspreading replicon particle lacking the fusion (F) protein gene (NiVΔF) as a vaccine in three small animal models of disease. A broad antibody response was detected that included immunoglobulin G (IgG) and IgA subtypes with demonstrable Fc-mediated effector function targeting multiple viral antigens. Single-dose intranasal vaccination up to 3 days before challenge prevented clinical signs and reduced virus levels in hamsters and immunocompromised mice; decreases were seen in tissues and mucosal secretions, critically decreasing potential for virus transmission. This virus replicon particle system provides a vital tool to the field and demonstrates utility as a highly efficacious and safe vaccine candidate that can be administered parenterally or mucosally to protect against lethal Nipah disease. |
Mouse models of Ebola virus tolerance and lethality: Characterization of CD-1 mice infected with wild-type, guinea pig-adapted, or mouse-adapted variants
Spengler JR , Welch SR , Ritter JM , Harmon JR , Coleman-McCray JD , Genzer SC , Nascimento Seixas J , Scholte FEM , Davies KA , Bradfute SB , Montgomery JM , Spiropoulou CF . Antiviral Res 2022 210 105496 Development of lethal models of Ebola virus disease has been achieved by the serial passage of virus isolates from human cases in mice and guinea pigs. Use of mice infected with non-adapted virus has been limited due to the absence of overt clinical disease. In recent years, newly recognized sequelae identified in human cases has highlighted the importance of continued investigations of non-lethal infection both in humans and animal models. Here, we revisit the use of rodent-adapted and non-adapted Ebola virus (EBOV) variants in mice to investigate infection tolerance and future utility of these models in pathogenesis and therapeutic intervention studies. We found that like non-adapted wild-type EBOV, guinea pig-adapted EBOV results in widespread tissue infection, variably associated with tissue pathology, and alterations in clinical and immunological analytes in the absence of overt disease. Notably, infection with either non-lethal variant does not greatly differ from lethal mouse-adapted EBOV until near the time end-point criteria are reached in these mice, supporting use of these models of virus tolerance for continued investigations of non-lethal infection and sequelae. |
Tissue replication and mucosal swab detection of Sosuga virus in Syrian hamsters in the absence of overt tissue pathology and clinical disease
Welch SR , Ritter JM , Schuh AJ , Genzer SC , Sorvillo TE , Harmon JR , Coleman-McCray JD , Jain S , Shrivastava-Ranjan P , Seixas JN , Estetter LB , Fair PS , Towner JS , Montgomery JM , Albariño CG , Spiropoulou CF , Spengler JR . Antiviral Res 2022 209 105490 Human infection with Sosuga virus (SOSV), a recently discovered pathogenic paramyxovirus, has been reported in one individual to date. No animal models of disease are currently available for SOSV. Here, we describe initial characterization of experimental infection in Syrian hamsters, including kinetics of virus dissemination and replication, and the corresponding clinical parameters, immunological responses, and histopathology. We demonstrate susceptibility of hamsters to infection in the absence of clinical signs or significant histopathologic findings in tissues. |
Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus
Durie IA , Tehrani ZR , Karaaslan E , Sorvillo TE , McGuire J , Golden JW , Welch SR , Kainulainen MH , Harmon JR , Mousa JJ , Gonzalez D , Enos S , Koksal I , Yilmaz G , Karakoc HN , Hamidi S , Albay C , Spengler JR , Spiropoulou CF , Garrison AR , Sajadi MM , Bergeron É , Pegan SD . Nat Commun 2022 13 (1) 7298 Crimean-Congo Hemorrhagic Fever Virus (CCHFV) causes a life-threatening disease with up to a 40% mortality rate. With no approved medical countermeasures, CCHFV is considered a public health priority agent. The non-neutralizing mouse monoclonal antibody (mAb) 13G8 targets CCHFV glycoprotein GP38 and protects mice from lethal CCHFV challenge when administered prophylactically or therapeutically. Here, we reveal the structures of GP38 bound with a human chimeric 13G8 mAb and a newly isolated CC5-17 mAb from a human survivor. These mAbs bind overlapping epitopes with a shifted angle. The broad-spectrum potential of c13G8 and CC5-17 and the practicality of using them against Aigai virus, a closely related nairovirus were examined. Binding studies demonstrate that the presence of non-conserved amino acids in Aigai virus corresponding region prevent CCHFV mAbs from binding Aigai virus GP38. This information, coupled with in vivo efficacy, paves the way for future mAb therapeutics effective against a wide swath of CCHFV strains. |
SARS-CoV-2 Infections and Reinfections among Fully Vaccinated and Unvaccinated University Athletes - 15 States, January - November 2021.
Good MK , Czarnik M , Harmon KG , Aukerman D , O'Neal CS , Day C , Goerl K , Sifre K , Fink S , Riggs MA . Clin Infect Dis 2022 75 S236-S242 BACKGROUND: Limited data currently exist on SARS-CoV-2 infections among fully vaccinated persons or reinfections in college-aged populations. CDC partnered with National Collegiate Athletic Association (NCAA) institutions to analyze retrospective data and present characteristics of positive COVID-19 cases among student athletes 18 years of age and older. METHODS: De-identified, individual-level data contributed by 21 universities on 1378 student athletes who tested positive for SARS-CoV-2 from January through November 2021 (pre-Omicron) were examined to determine percentages of infection among unvaccinated, partially vaccinated, and fully vaccinated individuals (breakthrough infections) as well as reinfections. Comparisons by demographic characteristics and regions were also made to further characterize these infections. RESULTS: Among the 1378 student athletes positive for SARS-CoV-2, 1070 (77.6%) were infected when unvaccinated and 22.4% (N = 308) were infected after full vaccination. There was a significant difference between Black (14.7%, n = 40) and White (23.9%, n = 168) student athletes who experienced a COVID-19 infection after being fully vaccinated (p < 0.01). Proportions of infections among fully vaccinated individuals did not differ statistically by sex (p = 0.06). CONCLUSIONS: This paper adds to the knowledge of COVID-19 infections among fully vaccinated individuals in college-aged populations. The level of infections among fully vaccinated student athletes indicates the need for maintaining precautions to prevent infection. Further study of COVID-19 vaccination, infection, and reinfection among the well-resourced and diverse population of student athletes might contribute further understanding of factors that play a role in health equity among young adults. |
Geometric mean serum cotinine concentrations confirm a continued decline in secondhand smoke exposure among U.S. nonsmokersNHANES 2003 to 2018
Caron KT , Zhu W , Bernert JT , Wang L , Blount BC , Dortch K , Hunter RE , Harmon T , Akins JR , Tsai J , Homa DM , Pirkle JL , Sosnoff CS . Int J Environ Res Public Health 2022 19 (10) The objective of this study was to examine long-term trends in serum cotinine (COT) concentrations, as a measure of secondhand smoke (SHS) exposure, in U.S. nonsmokers using data from the National Health and Nutrition Examination Surveys (NHANES) from 2003 to 2018. We analyzed NHANES serum COT results from 8 continuous NHANES 2 year cycles from 2003 to 2018 using a liquid chromatography–tandem mass spectrometry assay that has been maintained continuously at the Centers for Disease Control and Prevention (CDC) since 1992. Serum COT concentrations (based on the geometric means) among nonsmokers in the U.S. decreased by an average of 11.0% (95% confidence interval (CI) [8.8%, 13.1%]; p < 0.0001) every 2 year cycle. From 2003 to 2018, serum COT concentrations in U.S. nonsmokers declined by 55.0%, from 0.065 ng/mL in 2003–2004 to 0.029 ng/mL in 2017–2018 (p < 0.0001). Significant decreases in serum COT concentrations were observed in all demographic groups. While disparities between these groups seems to be shrinking over time, several previously observed disparities in SHS exposure remain in 2017–2018. Serum COT concentrations of the non-Hispanic Black population remained higher than those of non-Hispanic Whites and Mexican Americans (p < 0.0001). Additionally, serum COT concentrations were significantly higher for children aged 3–5 years than other age groups (p ≤ 0.0002), and men continued to have significantly higher serum COT concentrations than women (p = 0.0384). While there is no safe level of exposure to SHS, the decrease in serum COT concentrations in the U.S. population as well as across demographic groupings represents a positive public health outcome and supports the importance of comprehensive smoke-free laws and policies for workplaces, public places, homes, and vehicles to protect nonsmokers from SHS exposure. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. |
Viral RNA and infectious virus in mucosal specimens from guinea pigs modeling early phases of lethal and non-lethal Lassa fever
Welch SR , Genzer SC , Coleman-McCray JD , Harmon JR , Scholte FEM , Montgomery JM , Spiropoulou CF , Spengler JR . Emerg Microbes Infect 2022 11 (1) 1-17 ABSTRACTLassa fever (LF) is endemic to broad regions of West Africa. Infection with Lassa virus (LASV), the etiologic agent of LF, results in a spectrum of clinical signs in humans, including severe and lethal hemorrhagic disease. Person-to-person transmission occurs through direct contact with body fluids or contaminated bedding and clothing. To investigate transmission risk in acute LASV infection, we evaluated viral RNA and infectious virus obtained from conjunctival, nasal, oral, genital, and rectal swab specimens from guinea pigs modeling lethal and non-lethal LF. Viral RNA and infectious virus were detected in all specimen types beginning 8 days post infection, prior to onset of fever. In the pre-clinical and clinical period, virus was isolated from a subset of nasal, oral, genital, and rectal swabs, and from all conjunctival swabs. Overall, conjunctival and nasal specimens most frequently yielded infectious virus. These findings indicate mucosal transmission risk based on virus isolation from various sites early in infection and support potential utility of minimally invasive specimen evaluation by RT-qPCR for LASV diagnostics. |
Defective Interfering Viral Particle Treatment Reduces Clinical Signs and Protects Hamsters from Lethal Nipah Virus Disease.
Welch SR , Spengler JR , Harmon JR , Coleman-McCray JD , Scholte FEM , Genzer SC , Lo MK , Montgomery JM , Nichol ST , Spiropoulou CF . mBio 2022 13 (2) e0329421 Defective interfering particles (DIs) contain a considerably smaller genome than the parental virus but retain replication competency. As DIs can directly or indirectly alter propagation kinetics of the parental virus, they offer a novel approach to antiviral therapy, capitalizing on knowledge from natural infection. However, efforts to translate in vitro inhibition to in vivo screening models remain limited. We investigated the efficacy of virus-like particles containing DI genomes (therapeutic infectious particles [TIPs]) in the Syrian hamster model of lethal Nipah virus (NiV) disease. We found that coadministering a high dose of TIPs intraperitoneally with virus challenge improved clinical course and reduced lethality. To mimic natural exposure, we also evaluated lower-dose TIP delivery and virus challenge intranasally, finding equally efficacious reduction in disease severity and overall lethality. Eliminating TIP replicative capacity decreased efficacy, suggesting protection via direct inhibition. These data provide evidence that TIP-mediated treatment can confer protection against disease and lethal outcome in a robust animal NiV model, supporting further development of TIP treatment for NiV and other high-consequence pathogens. IMPORTANCE Here, we demonstrate that treatment with defective interfering particles (DIs), a natural by-product of viral infection, can significantly improve the clinical course and outcome of viral disease. When present with their parental virus, DIs can directly or indirectly alter viral propagation kinetics and exert potent inhibitory properties in cell culture. We evaluated the efficacy of a selection of virus-like particles containing DI genomes (TIPs) delivered intranasally in a lethal hamster model of Nipah virus disease. We demonstrate significantly improved clinical outcomes, including reduction in both lethality and the appearance of clinical signs. This work provides key efficacy data in a robust model of Nipah virus disease to support further development of TIP-mediated treatment against high-consequence viral pathogens. |
Lassa virus replicon particle vaccine protects strain 13/N guinea pigs against challenge with geographically and genetically diverse viral strains.
Spengler JR , Kainulainen MH , Welch SR , Coleman-McCray JAD , Harmon JR , Condrey JA , Scholte FEM , Nichol ST , Montgomery JM , Albariño CG , Spiropoulou CF . J Infect Dis 2022 226 (9) 1545-1550 Lassa virus (LASV) causes mild to severe hemorrhagic fever disease in humans. Strain 13/N guinea pigs are highly susceptible to infection with LASV strain Josiah (clade IV), providing a critical model system for therapeutics and vaccine development. To develop additional models of disease, we detail the clinical course in guinea pigs infected with 5 geographically and genetically diverse LASV strains. Two of the developed models (LASV clades II and III) were then used to evaluate efficacy of a virus replicon particle (VRP) vaccine against heterologous LASV challenge, demonstrating complete protection against clinical disease after a single vaccination dose. |
Identification and characterization of Rift Valley fever virus-specific T cells reveals a dependence on CD40/CD40L interactions for prevention of encephalitis
Barbeau DJ , Cartwright HN , Harmon JR , Spengler JR , Spiropoulou CF , Sidney J , Sette A , McElroy AK . J Virol 2021 95 (23) Jvi0150621 Rift Valley fever virus (RVFV) is an arbovirus found throughout Africa. It causes disease that is typically mild and self-limiting; however, some infected individuals experience severe manifestations, including hepatitis, encephalitis, or even death. Reports of RVFV encephalitis are notable amongst immunosuppressed individuals, suggesting a role for adaptive immunity in preventing this severe complication. This phenomenon has been modeled in C57BL/6 mice depleted of CD4 T cells prior to infection with DelNSs RVFV (RVFV containing a deletion of NSs), resulting in late-onset encephalitis accompanied by high levels of viral RNA in the brain in 30% of animals. In this study, we sought to define the specific type(s) of CD4 T cells that mediate protection from RVFV encephalitis. The viral epitopes targeted by CD4 and CD8 T cells were defined in C57BL/6 mice, and tetramers for both CD4 and CD8 T cells were generated. RVFV-specific CD8 T cells were expanded and of a cytotoxic and proliferating phenotype in the liver following infection. RVFV-specific CD4 T cells were identified in the liver and spleen following infection and phenotyped as largely Th1 or Tfh subtypes. Knock-out mice lacking various aspects of pathways important in Th1 and Tfh development and function were used to demonstrate that T-bet, CD40, CD40L, and MHCII mediated protection from RVFV encephalitis, while IFN-γ and IL-12 were dispensable. Virus-specific antibody responses correlated with protection from encephalitis in all mouse strains, suggesting that Tfh-B cell interactions modulate clinical outcome in this model. Importance: The prevention of RVFV encephalitis requires intact adaptive immunity. In this study we develop reagents to detect RVFV-specific T cells and provide evidence for Tfh cells and CD40/CD40L interactions as critical mediators of this protection. |
Correlates of plasma concentrations of per- and poly-fluoroalkyl substances among reproductive-aged Black women
Wise LA , Wesselink AK , Schildroth S , Calafat AM , Bethea TN , Geller RJ , Coleman CM , Fruh V , Henn BC , Botelho JC , Harmon QE , Thirkill M , Wegienka GR , Baird DD . Environ Res 2021 203 111860 BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used in commercial and consumer goods. Black women are underrepresented in studies of PFAS exposure. METHODS: We performed a cross-sectional analysis of correlates of plasma PFAS concentrations among 1499 Black women aged 23-35 participating in the Study of Environment, Lifestyle, and Fibroids (SELF), a Detroit-based cohort study. At baseline (2010-2012), participants provided questionnaire data on socio-demographics; behaviors; diet; and menstrual, contraceptive, and reproductive histories. Using mass spectrometry in non-fasting plasma samples collected at enrollment, we quantified several PFAS, including perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), and 2-N-methyl-perfluorooctane sulfonamido acetate (MeFOSAA). We used linear regression to calculate percentage differences (%D) and 95 % confidence intervals (CIs) for associations between selected correlates and PFAS concentrations, adjusting for all other correlates. RESULTS: PFHxS, PFOS, PFOA, and PFNA were detected in ≥97 % of women; PFDA in 86 %; MeFOSAA in 70 %; and PFUnDA in 52 %. Age, income, education, and intakes of water, alcohol, and seafood were positively associated with several PFAS. Current smoking was positively associated with MeFOSAA. Body mass index was inversely associated with most PFAS, except PFHxS. Strong inverse associations (%D; 95 % CI) were observed between parity (≥3 vs. 0 births) and PFHxS (-34.7; -43.0, -25.1) and PFOA (-33.1; -39.2, -26.3); breastfeeding duration (≥6 months vs. nulliparous) and PFOA (-31.1; -37.8, -23.7), PFHxS (-24.2; -34.5, -12.3), and PFOS (-18.4; -28.3, -7.1); recent birth (<2 years ago vs. nulliparous) and PFOA (-33.1; -39.6, -25.8), PFHxS (-29.3; -39.0, -18.1), PFNA (-25.2; -32.7, -16.8), and PFOS (-18.3; -28.3, -6.9); and intensity of menstrual bleed (heavy vs. light) and PFHxS (-18.8; -28.3, -8.2), PFOS (-16.4; -24.9, -7.1), PFNA (-10.5; -17.8, -2.6), and PFOA (-10.0; -17.2, -2.1). Current use of depot medroxyprogesterone acetate (DMPA) was positively associated with PFOS (20.2; 1.4, 42.5), PFOA (16.2; 1.5, 33.0), and PFNA (15.3; 0.4, 32.4). CONCLUSIONS: Reproductive factors that influence PFAS elimination showed strong associations with several PFAS (reduced concentrations with parity, recent birth, lactation, heavy menstrual bleeding; increased concentrations with DMPA use). These data contribute to the sparse literature on PFAS exposure among Black women. |
Urinary concentrations of phenols, parabens, and triclocarban in relation to uterine leiomyomata incidence and growth
Wesselink AK , Weuve J , Fruh V , Bethea TN , Claus Henn B , Harmon QE , Hauser R , Williams PL , Calafat AM , McClean M , Baird DD , Wise LA . Fertil Steril 2021 116 (6) 1590-1600 OBJECTIVE: To examine the association of urinary concentrations of phenols, parabens, and triclocarban with incidence and growth of uterine leiomyomata (UL; fibroids). DESIGN: Case-cohort study, nested within the Study of Environment, Lifestyle, and Fibroids, a prospective cohort study. SETTING: Clinic visits at baseline and every 20 months for 60 months. PATIENT(S): 754 Black women aged 23-35 years residing in the Detroit, Michigan area (enrolled during 2010-2012). INTERVENTION: None. MAIN OUTCOME MEASURE(S): At each study visit, women underwent transvaginal ultrasound for measurement of UL incidence and growth and provided urine specimens in which we quantified concentrations of seven phenols, four parabens, and triclocarban. We used Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs) characterizing the relation of urinary biomarker concentrations with UL incidence during the 60 months of follow-up. In a subset of UL detected and measured at multiple time points, we used linear regression to assess the associations between biomarker concentrations and UL growth. RESULT(S): Urinary biomarker concentrations were generally inversely associated with UL incidence, but the associations were weak and nonmonotonic. For example, hazard ratios comparing concentrations ≥90th with <50th percentile were 0.77 (95% CI: 0.46, 1.27) for bisphenol A, 0.72 (95% CI: 0.40, 1.28) for bisphenol S, and 0.76 (95% CI: 0.43, 1.33) for methylparaben. Biomarker concentrations were not strongly associated with UL growth. CONCLUSION(S): In this study of reproductive-aged Black women, urinary phenols, parabens, and triclocarban biomarkers were neither strongly nor consistently associated with UL incidence and growth. |
Viral replicon particles protect IFNAR(-/-) mice against lethal Crimean-Congo hemorrhagic fever virus challenge three days after vaccination
Spengler JR , Welch SR , Scholte FEM , Rodriguez SE , Harmon JR , Coleman-McCray JD , Nichol ST , Montgomery JM , Bergeron É , Spiropoulou CF . Antiviral Res 2021 191 105090 Crimean-Congo hemorrhagic fever virus (CCHFV) causes mild to severe and fatal disease in humans. Person-to-person transmission is common, necessitating the availability of rapidly deliverable therapeutic and prophylactic interventions to mitigate CCHFV spread. Previously, we showed complete protection using one dose of a viral replicon particle (VRP) vaccine administered 28 days before CCHFV challenge. In order to determine the utility of the VRP vaccine for rapid vaccination protocols, we assessed the efficacy of such vaccination administered at various intervals relative to challenge in IFNAR(-/-) mice. Unvaccinated mice uniformly succumbed to disease by 8 days post infection (dpi). All mice vaccinated 14, 7, or 3 days prior to CCHFV challenge survived infection. Mice vaccinated -14 or -7 dpi were fully protected from clinical disease, whereas mice inoculated -3 dpi developed signs of disease prior to recovering to baseline values 5-9 dpi. These data support the utility of the VRP vaccine for modified short course vaccination protocols to protect against disease and severe outcomes. |
Epidemiology of Chronic Effects of Traumatic Brain Injury.
Haarbauer-Krupa J , Pugh MJ , Prager EM , Harmon N , Wolfe J , Yaffe KC . J Neurotrauma 2021 38 (23) 3235-3247 Although many patients diagnosed with traumatic brain injury (TBI), particularly mild TBI, recover from their symptoms within a few weeks, a small but meaningful subset experience symptoms that persist for months or years after injury and significantly impact quality of life for the individual and their family. The factors associated with an increased likelihood of negative TBI outcomes include not only characteristics of the injury and injury mechanism, but also the individual's age, pre-injury status, comorbid conditions, environment, and propensity for resilience. In this article, as part of the Brain Trauma Blueprint: TBI State of the Science framework, we examine the epidemiology of long-term outcomes of TBI, including incidence, prevalence, and risk factors. We identify the need for increased longitudinal, global, standardized, and validated assessments on incidence, recovery, and treatments, as well as standardized assessments of the influence of genetics, race, ethnicity, gender, and environment on TBI outcomes. By identifying how epidemiological factors contribute to TBI outcomes in different groups of people and potentially impact differential disease progression, we can guide investigators and clinicians towards more precise patient diagnosis along with tailored management and improve clinical trial designs, data evaluation and patient selection criteria. |
Time from Start of Quarantine to SARS-CoV-2 Positive Test Among Quarantined College and University Athletes - 17 States, June-October 2020.
Atherstone C , Peterson ML , Malone M , Honein MA , MacNeil A , O'Neal CS , Paul S , Harmon KG , Goerl K , Wolfe CR , Casani J , Barrios LC . MMWR Morb Mortal Wkly Rep 2021 70 (1) 7-11 To safely resume sports, college and university athletic programs and regional athletic conferences created plans to mitigate transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). Mitigation measures included physical distancing, universal masking, and maximizing outdoor activity during training; routine testing; 10-day isolation of persons with COVID-19; and 14-day quarantine of athletes identified as close contacts* of persons with confirmed COVID-19. Regional athletic conferences created testing and quarantine policies based on National Collegiate Athletic Association (NCAA) guidance (1); testing policies varied by conference, school, and sport. To improve compliance with quarantine and reduce the personal and economic burden of quarantine adherence, the quarantine period has been reduced in several countries from 14 days to as few as 5 days with testing (2) or 10 days without testing (3). Data on quarantined athletes participating in NCAA sports were used to characterize COVID-19 exposures and assess the amount of time between quarantine start and first positive SARS-CoV-2 test result. Despite the potential risk for transmission from frequent, close contact associated with athletic activities (4), more athletes reported exposure to COVID-19 at social gatherings (40.7%) and from roommates (31.7%) than they did from exposures associated with athletic activities (12.7%). Among 1,830 quarantined athletes, 458 (25%) received positive reverse transcription-polymerase chain reaction (RT-PCR) test results during the 14-day quarantine, with a mean of 3.8 days from quarantine start (range = 0-14 days) until the positive test result. Among athletes who had not received a positive test result by quarantine day 5, the probability of having a positive test result decreased from 27% after day 5 to <5% after day 10. These findings support new guidance from CDC (5) in which different options are provided to shorten quarantine for persons such as collegiate athletes, especially if doing so will increase compliance, balancing the reduced duration of quarantine against a small but nonzero risk for postquarantine transmission. Improved adherence to mitigation measures (e.g., universal masking, physical distancing, and hand hygiene) at all times could further reduce exposures to SARS-CoV-2 and disruptions to athletic activities because of infections and quarantine (1,6). |
Asymptomatic Infection of Marburg Virus Reservoir Bats Is Explained by a Strategy of Immunoprotective Disease Tolerance.
Guito JC , Prescott JB , Arnold CE , Amman BR , Schuh AJ , Spengler JR , Sealy TK , Harmon JR , Coleman-McCray JD , Kulcsar KA , Nagle ER , Kumar R , Palacios GF , Sanchez-Lockhart M , Towner JS . Curr Biol 2020 31 (2) 257-270 e5 Marburg virus (MARV) is among the most virulent pathogens of primates, including humans. Contributors to severe MARV disease include immune response suppression and inflammatory gene dysregulation ("cytokine storm"), leading to systemic damage and often death. Conversely, MARV causes little to no clinical disease in its reservoir host, the Egyptian rousette bat (ERB). Previous genomic and in vitro data suggest that a tolerant ERB immune response may underlie MARV avirulence, but no significant examination of this response in vivo yet exists. Here, using colony-bred ERBs inoculated with a bat isolate of MARV, we use species-specific antibodies and an immune gene probe array (NanoString) to temporally characterize the transcriptional host response at sites of MARV replication relevant to primate pathogenesis and immunity, including CD14(+) monocytes/macrophages, critical immune response mediators, primary MARV targets, and skin at the inoculation site, where highest viral loads and initial engagement of antiviral defenses are expected. Our analysis shows that ERBs upregulate canonical antiviral genes typical of mammalian systems, such as ISG15, IFIT1, and OAS3, yet demonstrate a remarkable lack of significant induction of proinflammatory genes classically implicated in primate filoviral pathogenesis, including CCL8, FAS, and IL6. Together, these findings offer the first in vivo functional evidence for disease tolerance as an immunological mechanism by which the bat reservoir asymptomatically hosts MARV. More broadly, these data highlight factors determining disparate outcomes between reservoir and spillover hosts and defensive strategies likely utilized by bat hosts of other emerging pathogens, knowledge that may guide development of effective antiviral therapies. |
Lassa virus antigen distribution and inflammation in the ear of infected strain 13/N guinea pigs
Huynh T , Gary JM , Welch SR , Coleman-McCray J , Harmon JR , Kainulainen MH , Bollweg BC , Ritter JM , Shieh WJ , Nichol ST , Zaki SR , Spiropoulou CF , Spengler JR . Antiviral Res 2020 183 104928 Sudden sensorineuronal hearing loss (SNHL) is reported in approximately one-third of survivors of Lassa fever (LF) and remains the most prominent cause of Lassa virus- (LASV) associated morbidity in convalescence. Using a guinea pig model of LF, and incorporating animals from LASV vaccine trials, we investigated viral antigen distribution and histopathology in the ear of infected animals to elucidate the pathogenesis of hearing loss associated with LASV infection. Antigen was detected only in animals that succumbed to disease and was found within structures of the inner ear that are intimately associated with neural detection and/or translation of auditory stimuli and in adjacent vasculature. No inflammation or viral cytopathic changes were observed in the inner ear or surrounding structures in these animals. In contrast, no viral antigen was detected in the ear of surviving animals. However, all survivors that exhibited clinical signs of disease during the course of infection developed perivascular mononuclear inflammation within and adjacent to the ear, indicating an ongoing inflammatory response in these animals that may contribute to hearing loss. These data contribute to the knowledge of LASV pathogenesis in the auditory system, support an immune-mediated process resulting in LASV-associated hearing loss, and demonstrate that vaccination protecting animals from clinical disease can also prevent infection-associated auditory pathology. |
The Crimean-Congo Hemorrhagic Fever Virus NSm Protein is Dispensable for Growth In Vitro and Disease in Ifnar -/- Mice.
Welch SR , Scholte FEM , Spengler JR , Ritter JM , Coleman-McCray JD , Harmon JR , Nichol ST , Zaki SR , Spiropoulou CF , Bergeron E . Microorganisms 2020 8 (5) Crimean-Congo hemorrhagic fever virus (CCHFV) is a tri-segmented, tick-borne nairovirus that causes disease of ranging severity in humans. The CCHFV M segment encodes a complex glycoprotein precursor (GPC) that undergoes extensive endoproteolytic cleavage, giving rise to two structural proteins (Gn and Gc) required for virus attachment and entry, and to multiple non-structural proteins (NSm, GP160, GP85, and GP38). The functions of these non-structural proteins remain largely unclear. Here, we investigate the role of NSm during infection by generating a recombinant CCHFV lacking the complete NSm domain (10200NSm) and observing CCHFV NSm replication in cell lines and pathogenicity in Ifnar(-/-) mice. Our data demonstrate that the NSm domain is dispensable for viral replication in vitro, and, despite the delayed onset of clinical signs, CCHFV lacking this domain caused severe or lethal disease in infected mice. |
Routine HIV test results in 6 US clinical laboratories using the recommended laboratory HIV testing algorithm with Geenius HIV 1/2 supplemental assay
Wesolowski LG , Chavez PR , Cardenas AM , Katayev A , Slev P , Valsamakis A , Wang YF , Yao JD , Dougherty C , Gillim-Ross L , Harmon C , Delaney KP . Sex Transm Dis 2020 47 S13-s17 BACKGROUND: Geenius HIV 1/2 Supplemental Assay (Geenius; Bio-Rad Laboratories) is the only Food and Drug Administration-approved HIV-1/HIV-2 antibody differentiation test for the second step in the HIV laboratory testing algorithm. We characterized the occurrence of true HIV-1 and HIV-2 infections as well as false results in 6 US clinical laboratories using Geenius. METHODS: We examined routine HIV testing outcome data from the time the laboratories began using the algorithm with Geenius until September 30, 2017. We calculated the positive predictive value for Geenius HIV-1 and HIV-2 reactivity separately. RESULTS: Of 5,046,684 specimens tested, 41,791 had reactive antigen/antibody test results. Most specimens with reactive antigen/antibody results were HIV-1 antibody-positive established infections (n = 32,421), 1,865 of which also had indeterminate HIV-2 bands present. Ninety-three specimens were HIV-2 antibody positive or untypable for HIV-1/HIV-2 antibody. Acute HIV-1 infections were found in 528 specimens; 881 specimens lacked the nucleic acid test to determine the possibility of acute HIV-1 infection. False-positive antigen/antibody test results were present in 7505 specimens. Few specimens (n = 363) had false-positive antigen/antibody results with indeterminate Geenius and negative HIV-1 nucleic acid test results. The positive predictive values of Geenius reactivity were 99.4% for HIV-1 and 4.3% for HIV-2. CONCLUSIONS: Routine testing using the laboratory testing algorithm with Geenius resulted in most specimens resolving as HIV negative or HIV-1 positive. The occurrence of indeterminate HIV-2 bands with a Geenius final assay interpretation of HIV-1 positive was more common than true HIV-2 infections. Reporting indeterminate HIV-2 results in this situation may cause confusion with interpreting HIV infection status. |
Rift Valley fever virus vaccination induces long-lived, antigen-specific human T cell responses
Harmon JR , Barbeau DJ , Nichol ST , Spiropoulou CF , McElroy AK . NPJ Vaccines 2020 5 (1) 17 Rift Valley fever virus (RVFV) is a zoonotic arbovirus of clinical significance in both livestock and humans. A formalin-inactivated virus preparation was initially developed for human use and tested in laboratory workers in the 1960s. Vaccination resulted in generation of neutralizing antibody titers in most recipients, but neutralization titers waned over time, necessitating frequent booster doses. In this study, T cell-based immune responses to the formalin-inactivated vaccine were examined in a cohort of seven individuals who received between 1 and 6 doses of the vaccine. RVFV-specific T cell responses were detectable up to 24 years post vaccination. Peripheral blood mononuclear cells from this cohort of individuals were used to map out the viral epitopes targeted by T cells in humans. These data provide tools for assessing human RVFV-specific T cell responses and are thus a valuable resource for future human RVFV vaccine efforts. |
Inhibition of Nipah Virus by Defective Interfering Particles.
Welch SR , Tilston NL , Lo MK , Whitmer SLM , Harmon JR , Scholte FEM , Spengler JR , Duprex WP , Nichol ST , Spiropoulou CF . J Infect Dis 2020 221 S460-S470 The error-prone nature of ribonucleic acid (RNA)-dependent RNA polymerases drives the diversity of RNA virus populations. Arising within this diversity is a subset of defective viral genomes that retain replication competency, termed defective interfering (DI) genomes. These defects are caused by aberrant viral polymerase reinitiation on the same viral RNA template (deletion DI species) or the nascent RNA strand (copyback DI species). Defective interfering genomes have previously been shown to alter the dynamics of a viral population by interfering with normal virus replication and/or by stimulating the innate immune response. In this study, we investigated the ability of artificially produced DI genomes to inhibit Nipah virus (NiV), a highly pathogenic biosafety level 4 paramyxovirus. High multiplicity of infection passaging of both NiV clinical isolates and recombinant NiV in Vero cells generated an extensive DI population from which individual DIs were identified using next-generation sequencing techniques. Assays were established to generate and purify both naturally occurring and in silico-designed DIs as fully encapsidated, infectious virus-like particles termed defective interfering particles (DIPs). We demonstrate that several of these NiV DIP candidates reduced NiV titers by up to 4 logs in vitro. These data represent a proof-of-principle that a therapeutic application of DIPs to combat NiV infections may be an alternative source of antiviral control for this disease. |
Griffithsin inhibits Nipah virus entry and fusion and can protect Syrian golden hamsters from lethal Nipah virus challenge
Lo MK , Spengler JR , Krumpe LRH , Welch SR , Chattopadhyay A , Harmon JR , Coleman-McCray JD , Scholte FEM , Hotard AL , Fuqua JL , Rose JK , Nichol ST , Palmer KE , O'Keefe BR , Spiropoulou CF . J Infect Dis 2020 221 S480-S492 Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis and respiratory disease in humans. There is currently no approved therapeutic for human use against NiV infection. Griffithsin (GRFT) is high-mannose oligosaccharide binding lectin that has shown in vivo broad-spectrum activity against viruses including severe acute respiratory syndrome coronavirus, human immunodeficiency virus 1, hepatitis C virus, and Japanese encephalitis virus. In this study, we evaluated the in vitro antiviral activities of GRFT and its synthetic trimeric tandemer (3mG) against NiV and other viruses from across 4 virus families. The 3mG had comparatively greater potency than GRFT against NiV due to its enhanced ability to block NiV glycoprotein-induced syncytia formation. Our initial in vivo prophylactic evaluation of an oxidation-resistant GRFT (Q-GRFT) showed significant protection against lethal NiV challenge in Syrian golden hamsters. Our results warrant further development of Q-GRFT and 3mG as potential NiV therapeutics. |
Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in IFNAR-/- mice
Welch SR , Ritter JM , McElroy AK , Harmon JR , Coleman-McCray JD , Scholte FEM , Kobinger GP , Bergeron E , Zaki SR , Nichol ST , Spengler JR , Spiropoulou CF . PLoS Pathog 2019 15 (12) e1008183 Crimean-Congo hemorrhagic fever virus (CCHFV, order Bunyavirales, family Nairoviridae, genus Orthonairovirus) is the tick-borne etiological agent of Crimean-Congo hemorrhagic fever (CCHF) in humans. Animals are generally susceptible to CCHFV infection but refractory to disease. Small animal models are limited to interferon-deficient mice, that develop acute fatal disease following infection. Here, using a ZsGreen1- (ZsG) expressing reporter virus (CCHFV/ZsG), we examine tissue tropism and dissemination of virus in interferon-alpha/beta receptor knock-out (Ifnar-/-) mice. We demonstrate that CCHFV/ZsG retains in vivo pathogenicity comparable to wild-type virus. Interestingly, despite high levels of viral RNA in all organs assessed, 2 distribution patterns of infection were observed by both fluorescence and immunohistochemistry (IHC), corresponding to the permissiveness of organ tissues. To further investigate viral dissemination and to temporally define cellular targets of CCHFV in vivo, mice were serially euthanized at different stages of disease. Flow cytometry was used to characterize CCHFV-associated alterations in hematopoietic cell populations and to classify infected cells in the blood, lymph node, spleen, and liver. ZsG signal indicated that mononuclear phagocytic cells in the lymphatic tissues were early targets of infection; in late-stage infection, overall, the highest levels of signal were detected in the liver, and ZsG was found in both antigen-presenting and lymphocyte cell populations. |
Alterations in blood chemistry levels associated with Nipah virus disease in the Syrian hamster model
Genzer SC , Welch SR , Scholte FEM , Harmon JR , Coleman-McCray JD , Lo MK , Montgomery JM , Nichol ST , Spiropoulou CF , Spengler JR . J Infect Dis 2019 221 S454-S459 Nipah virus ([NiV] family Paramyxoviridae, genus Henipavirus) infection can cause severe respiratory and neurological disease in humans. The pathophysiology of disease is not fully understood, and it may vary by presentation and clinical course. In this study, we investigate changes in blood chemistry in NiV-infected Syrian hamsters that survived or succumbed to disease. Increased sodium and magnesium and decreased albumin and lactate levels were detected in animals euthanized with severe clinical disease compared with mock-infected controls. When subjects were grouped by clinical syndrome, additional trends were discernable, highlighting changes associated with either respiratory or neurological disease. |
Evaluation of a single-dose nucleoside-modified messenger RNA vaccine encoding hendra virus-soluble glycoprotein against lethal Nipah virus challenge in Syrian Hamsters
Lo MK , Spengler JR , Welch SR , Harmon JR , Coleman-Mccray JD , Scholte FEM , Shrivastava-Ranjan P , Montgomery JM , Nichol ST , Weissman D , Spiropoulou CF . J Infect Dis 2019 221 S493-S498 In the absence of approved vaccines and therapeutics for use in humans, Nipah virus continues to cause fatal outbreaks of encephalitis and respiratory disease in Bangladesh and India on a near-annual basis. We determined that a single dose of a lipid nanoparticle nucleoside-modified messenger RNA vaccine encoding the soluble Hendra virus glycoprotein protected up to 70% of Syrian hamsters from lethal NiV challenge, despite animals having suboptimally primed immune responses before challenge. These data provide a foundation from which to optimize future messenger RNA vaccination studies against NiV and other highly pathogenic viruses. |
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