Browsing by Author "Hurst, Jillian H"
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Item Open Access Age-related changes in the nasopharyngeal microbiome are associated with SARS-CoV-2 infection and symptoms among children, adolescents, and young adults.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022-03-05) Hurst, Jillian H; McCumber, Alexander W; Aquino, Jhoanna N; Rodriguez, Javier; Heston, Sarah M; Lugo, Debra J; Rotta, Alexandre T; Turner, Nicholas A; Pfeiffer, Trevor S; Gurley, Thaddeus C; Moody, M Anthony; Denny, Thomas N; Rawls, John F; Clark, James S; Woods, Christopher W; Kelly, Matthew SBackground
Children are less susceptible to SARS-CoV-2 infection and typically have milder illness courses than adults, but the factors underlying these age-associated differences are not well understood. The upper respiratory microbiome undergoes substantial shifts during childhood and is increasingly recognized to influence host defense against respiratory pathogens. Thus, we sought to identify upper respiratory microbiome features associated with SARS-CoV-2 infection susceptibility and illness severity.Methods
We collected clinical data and nasopharyngeal swabs from 285 children, adolescents, and young adults (<21 years of age) with documented SARS-CoV-2 exposure. We used 16S ribosomal RNA gene sequencing to characterize the nasopharyngeal microbiome and evaluated for age-adjusted associations between microbiome characteristics and SARS-CoV-2 infection status and respiratory symptoms.Results
Nasopharyngeal microbiome composition varied with age (PERMANOVA, p<0.001, R 2=0.06) and between SARS-CoV-2-infected individuals with and without respiratory symptoms (PERMANOVA, p=0.002, R 2=0.009). SARS-CoV-2-infected participants with Corynebacterium/Dolosigranulum-dominant microbiome profiles were less likely to have respiratory symptoms than infected participants with other nasopharyngeal microbiome profiles (odds ratio: 0.38, 95% confidence interval: 0.18-0.81). Using generalized joint attributed modeling, we identified nine bacterial taxa associated with SARS-CoV-2 infection and six taxa that were differentially abundant among SARS-CoV-2-infected participants with respiratory symptoms; the magnitude of these associations was strongly influenced by age.Conclusions
We identified interactive relationships between age and specific nasopharyngeal microbiome features that are associated with SARS-CoV-2 infection susceptibility and symptoms in children, adolescents, and young adults. Our data suggest that the upper respiratory microbiome may be a mechanism by which age influences SARS-CoV-2 susceptibility and illness severity.Item Open Access Age-related changes in the upper respiratory microbiome are associated with SARS-CoV-2 susceptibility and illness severity.(medRxiv, 2021-03-23) Hurst, Jillian H; McCumber, Alexander W; Aquino, Jhoanna N; Rodriguez, Javier; Heston, Sarah M; Lugo, Debra J; Rotta, Alexandre T; Turner, Nicholas A; Pfeiffer, Trevor S; Gurley, Thaddeus C; Moody, M Anthony; Denny, Thomas N; Rawls, John F; Woods, Christopher W; Kelly, Matthew SChildren are less susceptible to SARS-CoV-2 and typically have milder illness courses than adults. We studied the nasopharyngeal microbiomes of 274 children, adolescents, and young adults with SARS-CoV-2 exposure using 16S rRNA gene sequencing. We find that higher abundances of Corynebacterium species are associated with SARS-CoV-2 infection and SARS-CoV-2-associated respiratory symptoms, while higher abundances of Dolosigranulum pigrum are present in SARS-CoV-2-infected individuals without respiratory symptoms. We also demonstrate that the abundances of these bacteria are strongly, and independently, associated with age, suggesting that the nasopharyngeal microbiome may be a potentially modifiable mechanism by which age influences SARS-CoV-2 susceptibility and severity. SUMMARY: Evaluation of nasopharyngeal microbiome profiles in children, adolescents, and young adults with a SARS-CoV-2-infected close contact identified specific bacterial species that vary in abundance with age and are associated with SARS-CoV-2 susceptibility and the presence of SARS-CoV-2-associated respiratory symptoms.Item Open Access Combining adult with pediatric patient data to develop a clinical decision support tool intended for children: leveraging machine learning to model heterogeneity.(BMC medical informatics and decision making, 2022-03) Sabharwal, Paul; Hurst, Jillian H; Tejwani, Rohit; Hobbs, Kevin T; Routh, Jonathan C; Goldstein, Benjamin ABackground
Clinical decision support (CDS) tools built using adult data do not typically perform well for children. We explored how best to leverage adult data to improve the performance of such tools. This study assesses whether it is better to build CDS tools for children using data from children alone or to use combined data from both adults and children.Methods
Retrospective cohort using data from 2017 to 2020. Participants include all individuals (adults and children) receiving an elective surgery at a large academic medical center that provides adult and pediatric services. We predicted need for mechanical ventilation or admission to the intensive care unit (ICU). Predictor variables included demographic, clinical, and service utilization factors known prior to surgery. We compared predictive models built using machine learning to regression-based methods that used a pediatric or combined adult-pediatric cohort. We compared model performance based on Area Under the Receiver Operator Characteristic.Results
While we found that adults and children have different risk factors, machine learning methods are able to appropriately model the underlying heterogeneity of each population and produce equally accurate predictive models whether using data only from pediatric patients or combined data from both children and adults. Results from regression-based methods were improved by the use of pediatric-specific data.Conclusions
CDS tools for children can successfully use combined data from adults and children if the model accounts for underlying heterogeneity, as in machine learning models.Item Open Access Congenital human cytomegalovirus infection is associated with decreased transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-07-14) Semmes, Eleanor C; Li, Shuk Hang; Hurst, Jillian H; Yang, Zidanyue; Niedzwiecki, Donna; Fouda, Genevieve G; Kurtzberg, Joanne; Walsh, Kyle M; Permar, Sallie RBackground
Placentally-transferred maternal IgG protects against pathogens in early life, yet vertically-transmitted infections can interfere with transplacental IgG transfer. Although human cytomegalovirus (HCMV) is the most common placentally-transmitted viral infection worldwide, the impact of congenital HCMV (cCMV) infection on transplacental IgG transfer has been underexplored.Methods
We evaluated total and antigen-specific maternal and cord blood IgG levels and transplacental IgG transfer efficiency in a U.S-based cohort of 93 mother-infant pairs including 27 cCMV-infected and 66 cCMV-uninfected pairs, of which 29 infants were born to HCMV-seropositive non-transmitting mothers and 37 to HCMV-seronegative mothers. Controls were matched on sex, race/ethnicity, maternal age, and delivery year.Results
Transplacental IgG transfer efficiency was decreased by 23% (95% CI 10-36%, p=0.0079) in cCMV-infected pairs and 75% of this effect (95% CI 28-174%, p=0.0085) was mediated by elevated maternal IgG levels (i.e., hypergammaglobulinemia) in HCMV-transmitting women. Despite reduced transfer efficiency, IgG levels were similar in cord blood from infants with and without cCMV infection.Conclusions
Our results indicate that cCMV infection moderately reduces transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia; however, infants with and without cCMV infection had similar antigen-specific IgG levels, suggesting comparable protection from maternal IgG acquired via transplacental transfer.Item Open Access Correction to: Combining adult with pediatric patient data to develop a clinical decision support tool intended for children: leveraging machine learning to model heterogeneity.(BMC medical informatics and decision making, 2022-05) Sabharwal, Paul; Hurst, Jillian H; Tejwani, Rohit; Hobbs, Kevin T; Routh, Jonathan C; Goldstein, Benjamin AFollowing publication of the original article [1], it was reported that part of the ‘Outcome Variable Definition’ and the entirety of the ‘Descriptive statistics’ subsection was missing. These two subsections are given below with the previously missing text highlighted in bold. The original article [1] has been updated. Outcome Variable Definition In the initial development of the CDS tool, we were tasked with predicting four outcomes related to hospital resource utilization: overall length of stay, admission to the intensive care unit (ICU), requirement for mechanical ventilation, and discharge to a skilled nursing facility. Because children are rarely discharged to a skilled nursing facility and evaluating continuous outcomes poses unique challenges, we focused on the two binary outcomes: admission to the ICU and requirement for mechanical ventilation. Statistical Analysis Descriptive statistics We compared the pediatric and adult patient populations. We report standardized mean differences (SMDs) where an SMD > 0.10 indicates that the two groups are out of balance.Item Open Access Cultivating Research Skills During Clinical Training to Promote Pediatric-Scientist Development.(Pediatrics, 2019-08) Hurst, Jillian H; Barrett, Katherine J; Kelly, Matthew S; Staples, Betty B; McGann, Kathleen A; Cunningham, Coleen K; Reed, Ann M; Gbadegesin, Rasheed A; Permar, Sallie RPhysician-scientists represent a critical component of the biomedical and health research workforce. However, the proportion of physicians who spend a significant amount of effort on scientific research has declined over the past 40 years. This trend has been particularly noticeable in pediatrics despite recent scientific work revealing that early life influences, exposures, and health status play a significant role in lifelong health and disease. To address this problem, the Duke University Department of Pediatrics developed the Duke Pediatric Research Scholars Program for Physician-Scientist Development (DPRS). The DPRS is focused on research training during pediatric residency and fellowship. We aim to provide sufficient research exposure and support to help scholars develop a research niche and scholarly products as well as identify the career pathways that will enable them to achieve their research goals. Herein, we describe the DPRS's organizational structure, core components, recruitment strategies, and initial results, and we discuss implementation challenges and solutions. Additionally, we detail the program's integration with the department's residency and fellowship training programs (with particular reference to the challenges of integrating research into small- to medium-sized residency programs) and describe the development and integration of related initiatives across Duke University School of Medicine. The program served as the basis for 2 successful National Institutes of Health Stimulating Access to Research in Residency (R38) applications, and we hope it will serve as a model to integrate formalized research training for residents and fellows who wish to pursue research careers in academic medicine.Item Open Access Genetic variation associated with childhood and adult stature and risk of MYCN-amplified neuroblastoma.(Cancer medicine, 2020-11) Semmes, Eleanor C; Shen, Erica; Cohen, Jennifer L; Zhang, Chenan; Wei, Qingyi; Hurst, Jillian H; Walsh, Kyle MBackground
Neuroblastoma is the most common pediatric solid tumor. MYCN-amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes.Methods
We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN-amplification status, and compared to 3390 European-ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature.Results
An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre-pubertal height, was associated with greater risk of MYCN-amplified neuroblastoma (OR = 1.14, P = .047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN-amplified neuroblastoma (OR = 0.87, P = .047). These associations persisted in case-case analyses comparing MYCN-amplified to MYCN-unamplified neuroblastoma. No polygenic height scores were associated with MYCN-unamplified neuroblastoma risk. Previously identified genome-wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10-3 ) and adult height (P = 8.9 × 10-3 ) in >250 000 UK Biobank study participants.Conclusions
Genetic propensity to taller childhood height and shorter adult height were associated with MYCN-amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN-amplified neuroblastoma etiology.Item Open Access Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection.(The Journal of clinical investigation, 2022-08) Semmes, Eleanor C; Miller, Itzayana G; Wimberly, Courtney E; Phan, Caroline T; Jenks, Jennifer A; Harnois, Melissa J; Berendam, Stella J; Webster, Helen; Hurst, Jillian H; Kurtzberg, Joanne; Fouda, Genevieve G; Walsh, Kyle M; Permar, Sallie RHuman cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank. We found that high-avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development.Item Open Access SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020-11-03) Hurst, Jillian H; Heston, Sarah M; Chambers, Hailey N; Cunningham, Hannah M; Price, Meghan J; Suarez, Lilianna; Crew, Carter G; Bose, Shree; Aquino, Jhoanna N; Carr, Stuart T; Griffin, S Michelle; Smith, Stephanie H; Jenkins, Kirsten; Pfeiffer, Trevor S; Rodriguez, Javier; DeMarco, C Todd; De Naeyer, Nicole A; Gurley, Thaddeus C; Louzao, Raul; Zhao, Congwen; Cunningham, Coleen K; Steinbach, William J; Denny, Thomas N; Lugo, Debra J; Moody, M Anthony; Permar, Sallie R; Rotta, Alexandre T; Turner, Nicholas A; Walter, Emmanuel B; Woods, Christopher W; Kelly, Matthew SBACKGROUND:Children with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children. METHODS:We conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay. RESULTS:Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have asthma (p=0.005), and more likely to have an infected sibling contact (p=0.001) than uninfected children. Children ages 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs. 48%; p=0.01) or adolescents (29% vs. 60%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p<0.0001), gastrointestinal (27% vs. 9%; p=0.002), and sensory symptoms (42% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.01]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children. CONCLUSIONS:Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.Item Open Access SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.(medRxiv, 2020-09-01) Hurst, Jillian H; Heston, Sarah M; Chambers, Hailey N; Cunningham, Hannah M; Price, Meghan J; Suarez, Liliana; Crew, Carter G; Bose, Shree; Aquino, Jhoanna N; Carr, Stuart T; Griffin, S Michelle; Smith, Stephanie H; Jenkins, Kirsten; Pfeiffer, Trevor S; Rodriguez, Javier; DeMarco, C Todd; De Naeyer, Nicole A; Gurley, Thaddeus C; Louzao, Raul; Cunningham, Coleen K; Steinbach, William J; Denny, Thomas N; Lugo, Debra J; Moody, M Anthony; Permar, Sallie R; Rotta, Alexandre T; Turner, Nicholas A; Walter, Emmanuel B; Woods, Christopher W; Kelly, Matthew SBACKGROUND: Children with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children. METHODS: We conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay. RESULTS: Of 382 children, 289 (76%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have a history of asthma (p=0.009), and more likely to have an infected sibling contact (p=0.0007) than uninfected children. Children ages 6-13 years were frequently asymptomatic (38%) and had respiratory symptoms less often than younger children (30% vs. 49%; p=0.008) or adolescents (30% vs. 59%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p=0.002), gastrointestinal (26% vs. 9%; p=0.003), and sensory symptoms (43% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.004]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children. CONCLUSIONS: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while a history of asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.Item Open Access Systematic analysis of F-box proteins reveals a new branch of the yeast mating pathway(Journal of Biological Chemistry) Rangarajan, Nambirajan; Gordy, Claire L; Askew, Lauren; Bevill, Samantha M; Elston, Timothy C; Errede, Beverly; Hurst, Jillian H; Kelley, Joshua B; Sheetz, Joshua B; Suzuki, Sara Kimiko; Valentin, Natalie H; Young, Everett; Dohlman, Henrik G