Publications by authors named "Bridgette Jones"

32 Publications

Outbreak of COVID-19 and interventions in a large jail - Cook County, IL, United States, 2020.

Am J Infect Control 2021 Apr 2. Epub 2021 Apr 2.

Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA. Electronic address:

Background: Correctional and detention facilities are disproportionately affected by COVID-19 due to shared space, contact between staff and detained persons, and movement within facilities. On March 18, 2020, Cook County Jail, one of the United States' largest, identified its first suspected case of COVID-19 in a detained person.

Methods: This analysis includes SARS-CoV-2 cases confirmed by molecular detection among detained persons and Cook County Sheriff's Office staff. We examined occurrence of symptomatic cases in each building and proportions of asymptomatic detained persons testing positive, and timing of interventions including social distancing, mask use, and expanded testing and show outbreak trajectory in the jail compared to case counts in Chicago.

Results: During March 1-April 30, 907 symptomatic and asymptomatic cases of SARS-CoV-2 infection were detected among detained persons (n = 628) and staff (n = 279). Among asymptomatic detained persons in quarantine, 23.6% tested positive. Programmatic activity and visitation stopped March 9, cells were converted into single occupancy beginning March 26, and universal masking was implemented for staff (April 2) and detained persons (April 13). Cases at the jail declined while cases in Chicago increased.

Discussion/conclusions: Aggressive intervention strategies coupled with widespread diagnostic testing of detained and staff populations can limit introduction and mitigate transmission of SARS-CoV-2 infection in correctional and detention facilities.
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http://dx.doi.org/10.1016/j.ajic.2021.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016534PMC
April 2021

The safety of asthma medications during pregnancy and lactation: Clinical management and research priorities.

J Allergy Clin Immunol 2021 Jun 10;147(6):2009-2020. Epub 2021 Mar 10.

Kaiser Permanente Medical Center, San Diego, Calif.

Asthma is one of the most common underlying diseases in women of reproductive age that can lead to potentially serious medical problems during pregnancy and lactation. A group of key stakeholders across multiple relevant disciplines was invited to take part in an effort to prioritize, strategize, and mobilize action steps to fill important gaps in knowledge regarding asthma medication safety in pregnancy and lactation. The stakeholders identified substantial gaps in the literature on the safety of asthma medications used during pregnancy and lactation and prioritized strategies to fill those gaps. Short-term action steps included linking data from existing complementary study designs (US and international claims data, single drug pregnancy registries, case-control studies, and coordinated systematic data systems). Long-term action steps included creating an asthma disease registry, incorporating the disease registry into electronic health record systems, and coordinating care across disciplines. The stakeholders also prioritized establishing new infrastructures/collaborations to perform research in pregnant and lactating women and to include patient perspectives throughout the process. To address the evidence gaps, and aid in populating product labels with data that inform clinical decision making, the consortium developed a plan to systematically obtain necessary data in the most efficient and timely manner.
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http://dx.doi.org/10.1016/j.jaci.2021.02.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185876PMC
June 2021

The Loud Silence of Racism: It is Killing Us All.

Am J Bioeth 2021 02;21(2):4-6

University of Missouri Kansas City School of Medicine.

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http://dx.doi.org/10.1080/15265161.2020.1864107DOI Listing
February 2021

Identification of Presymptomatic and Asymptomatic Cases Using Cohort-Based Testing Approaches at a Large Correctional Facility-Chicago, Illinois, USA, May 2020.

Clin Infect Dis 2021 03;72(5):e128-e135

Cermak Health Services, Chicago, Illinois, USA.

Background: Coronavirus disease 2019 (COVID-19) continues to cause significant morbidity and mortality worldwide. Correctional and detention facilities are at high risk of experiencing outbreaks. We aimed to evaluate cohort-based testing among detained persons exposed to laboratory-confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to identify presymptomatic and asymptomatic cases.

Methods: During 1-19 May 2020, 2 testing strategies were implemented in 12 tiers or housing units of the Cook County Jail, Chicago, Illinois. Detained persons were approached to participate in serial testing (n = 137) and offered tests at 3 time points over 14 days (day 1, days 3-5, and days 13-14). The second group was offered a single test and interview at the end of a 14-day quarantine period (day 14 group) (n = 87).

Results: 224 detained persons were approached for participation and, of these, 194 (87%) participated in ≥1 interview and 172 (77%) had ≥1 test. Of the 172 tested, 19 were positive for SARS-CoV-2. In the serial testing group, 17 (89%) new cases were detected, 16 (84%) on day 1, 1 (5%) on days 3-5, and none on days 13-14; in the day 14 group, 2 (11%) cases were identified. More than half (12/19; 63%) of the newly identified cases were presymptomatic or asymptomatic.

Conclusions: Our findings highlight the utility of cohort-based testing promptly after initiating quarantine within a housing tier. Cohort-based testing efforts identified new SARS-CoV-2 asymptomatic and presymptomatic infections that may have been missed by symptom screening alone.
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http://dx.doi.org/10.1093/cid/ciaa1802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799274PMC
March 2021

Network Characteristics and Visualization of COVID-19 Outbreak in a Large Detention Facility in the United States - Cook County, Illinois, 2020.

MMWR Morb Mortal Wkly Rep 2020 Nov 6;69(44):1625-1630. Epub 2020 Nov 6.

Correctional and detention facilities have been disproportionately affected by coronavirus disease 2019 (COVID-19) because of shared space and movement of staff members and detained persons within facilities (1,2). During March 1-April 30, 2020, at Cook County Jail in Chicago, Illinois, >900 COVID-19 cases were diagnosed across all 10 housing divisions, representing 13 unique buildings. Movement within the jail was examined through network analyses and visualization, a field that examines elements within a network and the connections between them. This methodology has been used to supplement contact tracing investigations for tuberculosis and to understand how social networks contribute to transmission of sexually transmitted infections (3-5). Movements and connections of 5,884 persons (3,843 [65%] detained persons and 2,041 [35%] staff members) at the jail during March 1-April 30 were analyzed. A total of 472 (12.3%) COVID-19 cases were identified among detained persons and 198 (9.7%) among staff members. Among 103,701 shared-shift connections among staff members, 1.4% occurred between persons with COVID-19, a percentage that is significantly higher than the expected 0.9% by random occurrence alone (p<0.001), suggesting that additional transmission occurred within this group. The observed connections among detained persons with COVID-19 were significantly lower than expected (1.0% versus 1.1%, p<0.001) when considering only the housing units in which initial transmission occurred, suggesting that the systematic isolation of persons with COVID-19 is effective at limiting transmission. A network-informed approach can identify likely points of high transmission, allowing for interventions to reduce transmission targeted at these groups or locations, such as by reducing convening of staff members, closing breakrooms, and cessation of contact sports.
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http://dx.doi.org/10.15585/mmwr.mm6944a3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643900PMC
November 2020

We continue to fail black children with asthma and allergic disease.

Ann Allergy Asthma Immunol 2020 04;124(4):305-306

Department of Pediatrics, University of Missouri-Kansas City, Divisions of Allergy, Asthma and Clinical Immunology and Pediatric Pharmacology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2020.02.004DOI Listing
April 2020

The Reliability of Histamine Pharmacodynamic Response Phenotype Classification in Children With Allergic Disease.

Front Pharmacol 2020 11;11:227. Epub 2020 Mar 11.

Division of Pediatric Pharmacology, Therapeutic Innovation, Children's Mercy Hospital, Kansas City, MO, United States.

We have identified distinct histamine pharmacodynamic response phenotypes in children with allergic disease utilizing histamine iontophoresis with laser Doppler (HILD). These response phenotypes may be relevant in guiding therapeutic decision making for agents targeting the allergic response pathways. However, the reliability of these response phenotypes has not been assessed. Therefore, we performed HILD in children with allergic rhinitis and/or asthma on two to three separate occasions. HILD response-time data were analyzed in NONMEM using a linked effect PKPD model. Examination of observed vs. classified response phenotypes predicted response plots and the sum of residuals. The intraclass correlation coefficient (ICC) was used to determine the reliability of phenotype classification. Eighty-two percent of children exhibited a reliable histamine response phenotype [intraclass correlation coefficient 0.77 (95% CI 0.44-0.93]. These preliminary results suggest moderate reliability of HILD response phenotype in children. Further exploration is needed to determine contributions to phenotype variability.
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http://dx.doi.org/10.3389/fphar.2020.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078102PMC
March 2020

Step-Up Therapy in Black Patients with Asthma.

N Engl J Med 2020 01;382(4):390

University of Missouri-Kansas City School of Medicine, Kansas City, MO

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http://dx.doi.org/10.1056/NEJMc1915819DOI Listing
January 2020

Pediatric Clinical Endpoint and Pharmacodynamic Biomarkers: Limitations and Opportunities.

Paediatr Drugs 2020 Feb;22(1):55-71

Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO, 64108, USA.

Medical research in children typically lags behind that of adult research in both quantity and quality. The conduct of rigorous clinical trials in children can raise ethical concerns because of children's status as a 'vulnerable' population. Moreover, carrying out studies in pediatrics also requires logistical considerations that rarely occur with adult clinical trials. Due to the relatively smaller number of pediatric studies to support evidence-based medicine, the practice of medicine in children is far more reliant upon expert opinion than in adult medicine. Children are at risk of not receiving the same level of benefits from precision medicine research, which has flourished with new technologies capable of generating large amounts of data quickly at an individual level. Although progress has been made in pediatric pharmacokinetics, which has led to safer and more effective dosing, gaps in knowledge still exists when it comes to characterization of pediatric disease and differences in pharmacodynamic response between children and adults. This review highlights three specific therapeutic areas where biomarker development can enhance precision medicine in children: asthma, type 2 diabetes mellitus, and pain. These 'case studies' are meant to update the reader on biomarkers used currently in the diagnosis and treatment of these conditions, and their shortcomings within a pediatric context. Current research on surrogate endpoints and pharmacodynamic biomarkers in the above therapeutic areas will also be described. These cases highlight the current lack in pediatric specific surrogate endpoints and pharmacodynamic biomarkers, as well as the research presently being conducted to address these deficiencies. We finally briefly highlight other therapeutic areas where further research in pediatric surrogate endpoints and pharmacodynamic biomarkers can be impactful to the care of children.
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http://dx.doi.org/10.1007/s40272-019-00375-1DOI Listing
February 2020

Increasing Resident Racial and Ethnic Diversity through Targeted Recruitment Efforts.

J Pediatr 2020 01;216:4-6

Department of Pediatrics, Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, MO.

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http://dx.doi.org/10.1016/j.jpeds.2019.10.015DOI Listing
January 2020

Chronic stress exposure among young African American children with asthma: Racism is a factor.

Ann Allergy Asthma Immunol 2019 11 3;123(5):507-508. Epub 2019 Sep 3.

Department of Behavioral Sciences and Health Education, Emory University Rollins School of Public Health, Atlanta, Georgia.

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http://dx.doi.org/10.1016/j.anai.2019.08.023DOI Listing
November 2019

The Impact of Environmental Chronic and Toxic Stress on Asthma.

Clin Rev Allergy Immunol 2019 Dec;57(3):427-438

Department of Pediatrics, University of Missouri Kansas City School of Medicine, Kansas City, USA.

Several factors have been associated with the development of asthma and asthma-related morbidity and mortality. Exposures in the environment such as allergens and air pollutants have traditionally been linked to the risk of asthma and asthma outcomes. More recent literature has identified chronic psychosocial stress as an additional environmental exposure to consider in relation to asthma. Adverse childhood events (ACEs) and chronic and toxic stress have been associated with chronic diseases such as cardiovascular disease, cancer, and chronic obstructive pulmonary disease. Chronic stress has also been shown to result in biological changes such as expression of immunologic genes, changes in expression of the beta-adrenergic (B2AR) and the glucocorticoid receptor (GR-α) genes, cytokine regulation, and alterations in the hypothalamic pituitary axis and cortisol levels which all may affect asthma pathophysiology and therapeutic response among patients exposed to chronic stress. Recent research has revealed associations between ACEs and chronic and toxic stress and asthma risk in pre-conception to early childhood as well as morbidity and response to asthma treatments among pediatric and adult age groups. As some populations are more significantly impacted by asthma such as racial and ethnic minority groups, the influence of psychosocial stress has also been explored as a potential factor responsible for observed disparities in asthma prevalence and outcomes among these groups which also experience higher rates of psychosocial stress. Racial discrimination has specifically been shown to affect asthma-related outcomes among minority groups. Interventions to address the impact of chronic and toxic stress such as yoga and meditation have been shown to improve asthma outcome measures. Chronic and toxic stress is an important environmental exposure to further consider as we continue to explore the differences in underlying asthma pathophysiology leading to various disease phenotypes among patients and clinical/therapeutic response to interventions and treatments.
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http://dx.doi.org/10.1007/s12016-019-08736-xDOI Listing
December 2019

Closing the gap: Understanding African American asthma knowledge and beliefs.

Ann Allergy Asthma Immunol 2018 10;121(4):458-463

Children's Mercy Hospital, Kansas City, Missouri.

Background: African American children are disproportionately affected by asthma (13% vs 8% non-Hispanic white Americans) and experience 30% higher asthma-related deaths than whites. Knowledge regarding asthma and asthma treatment among African Americans has been postulated as a potential contributor to this observed health disparity. Compared with the amount of studies on asthma, few investigations provide insight into the baseline knowledge and beliefs of African Americans regarding asthma.

Objective: Assess knowledge and beliefs regarding asthma symptoms, diagnosis, treatment, prognosis, and stigmas in a general community sample of African Americans.

Methods: Using community-based participatory research techniques, we developed and implemented a cross-sectional survey to explore asthma knowledge and beliefs among African American adults in a Midwestern city.

Results: Among the 158 African American adults who completed the survey, general asthma knowledge was good, with awareness of the genetic contribution to asthma and general asthma symptomatology (eg, 92% aware of nighttime cough as a symptom). However, asthma-related misconceptions were also revealed. Thirty-three percent of respondents were concerned about addiction to asthma medication, and 60% of respondents believed that inhaled corticosteroids were dangerous or did not know.

Conclusion: This study reveals important insights into asthma knowledge and beliefs among African Americans that may be used to address disparities in asthma outcomes in this population.
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http://dx.doi.org/10.1016/j.anai.2018.07.015DOI Listing
October 2018

Understanding the biology of disease in underserved children with asthma: The missing piece of the health disparity puzzle.

Ann Allergy Asthma Immunol 2017 08;119(2):99-100

Department of Pediatrics, Divisions of Allergy/Asthma/Immunology and Pediatric Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, University of Missouri, Kansas City, MO. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2017.06.007DOI Listing
August 2017

Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma.

Front Pharmacol 2016 4;7:524. Epub 2017 Jan 4.

Department of Pediatrics University of Missouri-Kansas City, Children's Mercy Hospitals and ClinicsKansas City, MO, USA; Division of Pediatric Pharmacology and Therapeutic Innovation, Children's Mercy Hospitals and ClinicsKansas City, MO, USA; Children's Mercy Hospitals and ClinicsKansas City, MO, USA.

There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model. DNA isolation and genotyping were performed among participants to detect known single nucleotide polymorphisms (SNPs) ( = 10) among genes () within the histamine pathway. General linear model was used to identify associations between histamine related genetic variants and measured histamine PD response parameters. Genotyping and HILD response profiles were completed for 163 children. were associated with Emax ( 47 CC genotype mean Emax 167.21 vs. CT/TT genotype mean Emax 139.20, = 0.04; 4107 CC genotype mean Emax 141.72 vs. CG/GG genotype mean Emax 156.09, = 0.005; -1639 CC genotype mean Emax 132.62 vs. CT/TT genotype mean Emax 155.3, = 0.02). In a stratified analysis among African American children only, and SNPs were also associated with PD response; 413 CC genotype was associated with lower Emax, = 0.009. We show for the first time that histamine pathway genetic variation is associated with measureable changes in histamine response in children with asthma. The variability in histamine response and impact of histamine pathway genotype is important to further explore in patients with asthma so as to improve disease phenotyping leading to more personalized treatments.
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http://dx.doi.org/10.3389/fphar.2016.00524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209333PMC
January 2017

If We Would Only Ask: How Henrietta Lacks Continues to Teach Us About Perceptions of Research and Genetic Research Among African Americans Today.

J Racial Ethn Health Disparities 2017 08 23;4(4):735-745. Epub 2016 Sep 23.

Department of Pediatrics, University of Missouri-Kansas City, 2401 Gillham Rd, Kansas City, MO, 64108, USA.

Background: African Americans are under-represented in research, and there are perceptions of unwillingness among African Americans to participate in research. We explored barriers to African American research participation.

Methods: We conducted a cross-sectional survey to explore knowledge and beliefs regarding medical and genetic research among adults (n = 169) at urban community events. Descriptive data were summarized by frequencies for survey responses.

Results: Only 13 % of respondents had ever been approached for research; 93 % of those who had been approached for research had participated. Eighty-six percent of those who had previous research experience indicated willingness to participate again vs. only 30 % among those with no research experience. Seventy-four percent had altruistic views of research; 28 % were concerned about truthfulness of researchers; 52 % feared incidental discoveries.

Conclusion: African Americans have favorable views of research; however, few are being engaged in studies. Effective interventions to address identified barriers may improve participation and lead to better health outcomes among African Americans.
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http://dx.doi.org/10.1007/s40615-016-0277-1DOI Listing
August 2017

Linkage and Genetic Association in Severe Asthma.

Immunol Allergy Clin North Am 2016 08;36(3):439-47

Division of Allergy, Asthma and Clinical Immunology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA.

A significant body of work in the genetics of asthma currently exists. However, current knowledge has not been clarifying in understanding the pathophysiology of asthma and therapeutic treatment of the disease. Severe asthma in adults and children is a significant burden in relation to disproportionate disease morbidity, mortality, and health utilization. This disease phenotype is not well understood; current effective treatment regimens are limited. Genetic studies may lead to improved understanding of the pathophysiology of severe asthma and identification of relevant subsets, which allow more targeted and effective therapies and the realization of Precision Medicine in asthma.
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http://dx.doi.org/10.1016/j.iac.2016.03.002DOI Listing
August 2016

Population pharmacokinetic/pharmacodynamic modeling of histamine response measured by histamine iontophoresis laser Doppler.

J Pharmacokinet Pharmacodyn 2016 08 15;43(4):385-93. Epub 2016 Jun 15.

Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults. However, due to the high sampling frequency (up to 40 Hz), the output files are usually too cumbersome to be directly used for further analysis. In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional maximum effect (Emax) model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094/min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1 flux unit; Emax, 13.4; concentration at half maximum effect (EC50) 31.1 mg/L. Covariate analysis indicated that age and race had significant influence on Tlag and EC50, respectively.
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http://dx.doi.org/10.1007/s10928-016-9478-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994972PMC
August 2016

Clinical and Pharmacologic Considerations for Guanfacine Use in Very Young Children.

J Child Adolesc Psychopharmacol 2016 08 19;26(6):498-504. Epub 2016 Feb 19.

3 Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Hospital , Kansas City, Missouri.

Objective: Guanfacine, in the immediate release form, remains a commonly used medication for the treatment of clinically significant hyperactivity, impulsivity, or disruptive behaviors. This article reviews the available literature regarding guanfacine use in very young children (<6 years of age), and explores some of the factors that may uniquely impact the clinical pharmacology of guanfacine in very young children and that deserve consideration when it is used in this patient population.

Methods: The authors performed electronic literature searches in PubMed through October 2015 using the terms attention-deficit/hyperactivity disorder, guanfacine, and alpha agonists. We also performed an informal review of the literature and used selected articles from relevant reference lists. The result was a broad, qualitative review of the literature, with a focus on specific factors regarding guanfacine use in very young children.

Results: Despite the fact that guanfacine is commonly used in very young children, there is a paucity of published studies that looked specifically at its use in this population. In reviewing the pharmacology of guanfacine, there are specific factors that may play a unique role in its disposition in very young children.

Conclusions: Guanfacine is an important medication option in very young children; however, there is a significant pharmacologic "information gap," and further research is needed to help establish appropriate, safe, and effective dosing of guanfacine in this population.
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http://dx.doi.org/10.1089/cap.2014.0159DOI Listing
August 2016

Cetirizine Quantification by High-Performance Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS).

Methods Mol Biol 2016 ;1383:115-20

Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO, 64108, USA.

A multiple reaction monitoring (MRM), positive ion electrospray ionization, LC/MS/MS method is described for the quantification of cetirizine. The compound was isolated from human plasma by protein precipitation using acetonitrile. Cetirizine d4 was used as an internal standard. Chromatographic conditions were achieved using a C18 column and a combination of ammonium acetate, water, and methanol as the mobile phase. MRMs were: cetirizine, 389.26 → 165.16, 201.09; cetirizine d4, 393.09 → 165.15, 201.10. Calibration curves were constructed by plotting the peak area ratios of the calibrators' target MRM transition area to labeled internal standard target MRM transition area versus concentration.
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http://dx.doi.org/10.1007/978-1-4939-3252-8_13DOI Listing
October 2016

Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

Am J Respir Cell Mol Biol 2015 Dec;53(6):802-9

1 Division of Allergy/Asthma/Immunology.

Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease.
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http://dx.doi.org/10.1165/rcmb.2014-0493OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742940PMC
December 2015

Genetic variation within the histamine pathway among patients with asthma--a pilot study.

J Asthma 2015 May 30;52(4):353-62. Epub 2014 Oct 30.

Division of Allergy/Asthma/Immunology .

Objective: Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine-related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway, and determine their association with asthma and HRH1 mRNA expression.

Methods: We enrolled children and adults (n = 93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for nine known SNPs in the HDC, HRH1, HRH4, HNMT and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher's exact test and Chi-square test were used to determine differences in allele, genotype and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p < 0.05.

Results: No difference was observed in genotype/allele frequency for the nine SNPs between subjects with and without asthma. The HNMT-1639C/-464C/314C/3'UTRA haplotype was more frequently observed in those without asthma than those with asthma (p = 0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p = 0.04).

Conclusions: Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings.
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http://dx.doi.org/10.3109/02770903.2014.973501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416071PMC
May 2015

Interpretation of food specific immunoglobulin E levels in the context of total IgE.

Ann Allergy Asthma Immunol 2013 Jul;111(1):20-4

Children's Mercy Hospitals and Clinics, Kansas City, Missouri 64108, USA.

Background: Food specific immunoglobulin E (IgE) (fsIgE) cut points are used in the evaluation of food allergies. Concomitant measurement of total IgE (tIgE) is traditionally not obtained. We anecdotally observed elevations in fsIgE mirroring tIgE increases, which may confound accurate interpretation.

Objective: To determine whether changes in tIgE were associated with fsIgE and whether predictions of fsIgE could be formulated based on tIgE.

Methods: We studied children younger than 18 years who had both tIgE and fsIgE (egg, n = 136; milk, n = 123; peanut, n = 201; soy, n = 55) obtained simultaneously on 1 or more occasion between January 2008 and February 2011. After institutional review board approval, natural log-transformed (ln) tIgE and fsIgE levels were analyzed using univariate and multivariate regression models to assess associations and predict fsIgE using tIgE and other covariates.

Results: Soy IgE levels were strongly correlated (ρ = 0.85, P < .001), whereas egg, milk, and peanut IgE levels were substantially correlated (ρ = 0.69, 0.69, and 0.66, respectively, P < .001) with tIgE. A 1-unit increase in ln(tIgE) was significantly correlated with unit increases in ln(egg IgE) (0.77), ln(milk IgE) (0.84), ln(peanut IgE) (0.87), and ln(soy IgE) (0.89) (P < .001). The ln(tIgE)-based univariate models could predict fsIgE in the validation data with strong (soy) and substantial (egg, milk, and peanut) predictive ability (P < .001).

Conclusion: Our study found significant and parallel relationships between tIgE and fsIgE levels to egg, milk, peanut, and soy. It underscores the importance of examining fsIgE levels in context of tIgE while making diagnostic and management decisions in children with food allergies.
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http://dx.doi.org/10.1016/j.anai.2013.05.012DOI Listing
July 2013

Variability of histamine pharmacodynamic response in children with allergic rhinitis.

J Clin Pharmacol 2013 Jul 16;53(7):731-7. Epub 2013 May 16.

Department of Paediatrics, University of Missouri, Kansas City, MO 64108, USA.

Histamine iontophoresis with laser Doppler monitoring (HILD) is a robust and dynamic surrogate for histamine microvasculature response. We characterized histamine pharmacodynamics in children using HILD. HILD was performed in 54 children with allergic rhinitis. A non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model was used to provide estimates for area under the effect curve (AUEC), maximal response over baseline (EffmaxNT), and time of EffmaxNT (Tmax). Data were placed in sub-groups by visualization of time vs. response relationships. ANOVA and regression analyses were used for sub-group comparisons. Three histamine response phenotypes were identified. One group demonstrated a hyper-responsive phenotype (higher Tmax, EffmaxNt and AUEC, P < .01). AUEC and EffmaxNT were more strongly associated in this group (r(2)  = 0.86) than the entire cohort (r(2)  = 0.64). These data demonstrate a hyper-responsive histamine phenotype via HILD. This finding is important to future pharmacologic studies of antihistamines.
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http://dx.doi.org/10.1002/jcph.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564401PMC
July 2013

Genetic variation in the TNFA promoter region and TNFA gene expression in subjects with asthma.

J Asthma 2013 Aug 13;50(6):541-7. Epub 2013 May 13.

Children's Mercy Hospital, Kansas City, MO, USA.

Objective: Asthma is a chronic disease that affects millions of people. Messenger RNA (mRNA) expression of specific inflammatory markers has been associated with asthma and corticosteroid response. Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, has been shown to have increased expression in airways of asthmatics and may be related to corticosteroid sensitivity. The purpose of this study was to determine how genetic variants within the promoter region of the TNFA gene differ between subjects with asthma and controls. We also investigated how genetic variation affects gene expression.

Methods: We enrolled 94 subjects between 5 to 54 years of age who met the inclusion and exclusion criteria. TNFA mRNA expression was determined by qRT-PCR on total RNA isolated from the buccal mucosa. Genotyping was performed for TNFA-1031T/C, -857C/T, and -308G/A on genomic DNA isolated from blood with commercially available assays. Gene expression was log-2 transformed and corrected with 2 normalization genes. General linear model, Chi-square test, Fisher's exact test, and Cochran-Mantel-Haenszel test were performed with p < .05.

Results: The TNFA-857C/T polymorphism is associated with asthma in this cohort. The TNFA-857 T allele is underrepresented in pediatric subjects with asthma relative to those without asthma (3% and 29% of individuals, respectively, p = .01). Furthermore, a TNFA haplotype combination containing -1031T/-857C/-308G and -1031T/-857T/-308G is associated with lower expression of TNF-α mRNA (p = .01) in pediatric subjects.

Conclusions: Presence of the TNFA-857T allele may be protective in the development of asthma and a haplotype combination that contains the TNFA-857T allele is associated with TNFA expression.
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http://dx.doi.org/10.3109/02770903.2013.792350DOI Listing
August 2013

Detecting gene expression in buccal mucosa in subjects with asthma versus subjects without asthma.

Pediatr Allergy Immunol 2013 Mar 1;24(2):138-43. Epub 2013 Mar 1.

Division of Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA.

Background: Differences in mRNA expression for inflammatory markers have been observed between subjects with asthma vs. controls and in relation to corticosteroid response. However, these studies utilized methods (e.g., bronchoscopy) that are too invasive to be used routinely in children and in the clinic. The primary purpose of this study was to determine the feasibility of obtaining RNA of adequate quantity and quality from buccal mucosa of children and adults for gene expression studies. Secondly, this study aimed to determine whether gene expression patterns in buccal mucosa are similar to those that have been observed in respiratory epithelium.

Methods: We enrolled 94 subjects with and without asthma between 5 and 54 years of age. Relative gene expression in buccal mucosa was determined with quantitative RT-PCR for the following genes: CCL2, EDN1, FKBP5, IL8, IFNAR2, NFKB1, RELA, SERPINB2, DENND1B, HRH1, ICAM1, ORMDL3, NR3C1, CLCA1, CRHR1, MUC5B, FCER2, POSTN, GAPDH, PPIA.

Results: mRNA Expression of the following genes was detected in buccal mucosa: CCL2, EDN1, FKBP5, IL8, IFNAR2, NFKB1, RELA, SERPINB2, DENND1B, HRH1, ICAM1, ORMDL3, NR3C1, GAPDH, PPIA. HRH1 was differentially expressed in adults with asthma vs. controls (p = 0.04), and EDN1 was differentially expressed in children with asthma vs. controls 12-18 years old (p = 0.03). A similar trend for HRH1 was observed in children 12-18 years old.

Conclusions: Buccal mucosa sampling is a reliable method for detecting changes in gene expression in patients with asthma. This non-invasive technique may serve as a valuable tool for diagnosing asthma and evaluating therapeutic response.
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http://dx.doi.org/10.1111/pai.12042DOI Listing
March 2013

Mixed modeling and sample size calculations for identifying housekeeping genes.

Stat Med 2013 Aug 26;32(18):3115-25. Epub 2013 Feb 26.

Research Development and Clinical Investigation, Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA.

Normalization of gene expression data using internal control genes that have biologically stable expression levels is an important process for analyzing reverse transcription polymerase chain reaction data. We propose a three-way linear mixed-effects model to select optimal housekeeping genes. The mixed-effects model can accommodate multiple continuous and/or categorical variables with sample random effects, gene fixed effects, systematic effects, and gene by systematic effect interactions. We propose using the intraclass correlation coefficient among gene expression levels as the stability measure to select housekeeping genes that have low within-sample variation. Global hypothesis testing is proposed to ensure that selected housekeeping genes are free of systematic effects or gene by systematic effect interactions. A gene combination with the highest lower bound of 95% confidence interval for intraclass correlation coefficient and no significant systematic effects is selected for normalization. Sample size calculation based on the estimation accuracy of the stability measure is offered to help practitioners design experiments to identify housekeeping genes. We compare our methods with geNorm and NormFinder by using three case studies. A free software package written in SAS (Cary, NC, U.S.A.) is available at http://d.web.umkc.edu/daih under software tab.
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http://dx.doi.org/10.1002/sim.5768DOI Listing
August 2013

Defining risk factors for red man syndrome in children and adults.

Pediatr Infect Dis J 2012 May;31(5):464-8

Department of Pediatrics, Medical Research, Children's Mercy Hospitals and Clinics and the University of Missouri-Kansas City, Kansas City, MO 64108, USA.

Background: Red man syndrome (RMS) is a well-known adverse reaction that occurs in pediatric patients receiving vancomycin, yet reported prevalence is varied, and characteristics and risk factors are not well understood. Our objective was to determine the prevalence, characteristics and risk factors for RMS in pediatric patients receiving vancomycin, including contributing genetic factors.

Methods: A multicenter retrospective study of 546 subjects (0.5-21 years) who received at least 1 dose of intravenous vancomycin was conducted. Demographic and symptom data were collected through chart review and parent/nurse report. Genotype analysis included 10 single nucleotide polymorphisms in the histamine pathway.

Results: RMS was observed in 77 (14%) subjects receiving vancomycin. Forty percent of subjects with RMS symptoms developed rash, pruritis and flushing, without hypotension. Antecedent antihistamine use was identified as a risk factor for RMS (P < 0.001). Multivariate regression analysis identified age > 2 years (P = 0.008), previous RMS (P < 0.001), vancomycin dose (P = 0.02) and vancomycin concentration (P = 0.017) as RMS risk factors, whereas African American race was protective (P = 0.011). We observed an apparent association between RMS and a single nucleotide polymorphism in the diamine oxidasegene (P = 0.044); however, no associations were revealed by multifactor dimensionality reduction analysis.

Conclusions: RMS is a common adverse event in children receiving vancomycin. Identified risk factors are Caucasian ethnicity, age ≥ 2 years, previous RMS history, vancomycin dose ≥ 10 mg/kg, vancomycin concentration ≥ 5 mg/mL and antecedent antihistamine use. Known genetic variants in histamine metabolism or receptors do not appear to be substantial contributors to risk of RMS.
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http://dx.doi.org/10.1097/INF.0b013e31824e10d7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3333837PMC
May 2012

Development of biomarkers to optimize pediatric patient management: what makes children different?

Biomark Med 2011 Dec;5(6):781-94

Division of Clinical Pharmacology & Medical Toxicology, Children's Mercy Hospitals & Clinics & University of Missouri-Kansas City, Kansas City, MO, USA.

Despite the frequent utilization of biomarkers in medical practice, there is a relative paucity of information regarding validated pediatric biomarkers. Frequently, biomarkers found to be efficacious in adults are extrapolated to the pediatric clinical setting without considering that the pathogenesis of many diseases is distinctly different in children, and ontogeny directly influences disease evolution and therapeutic response in children. New and innovative approaches are necessary to provide reliable, validated biomarkers that can be used to improve and advance pediatric medical care.
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http://dx.doi.org/10.2217/bmm.11.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321646PMC
December 2011

The impact of pharmacogenetics in the treatment of allergic disease and asthma.

Mo Med 2011 Sep-Oct;108(5):361-5

Department of Pediatrics, Children's Mercy Hospital and Clinics, USA.

Personalized medicine includes the application of genomic information in predicting disease and therapeutic response to ultimately individualize patient care. Pharmacogenetics is key in achieving true personalized care. However, the clinical applicability of genetic testing to "everyday medicine" is yet to be realized. This paper will discuss areas in allergic/inflammatory disease that have been impacted by pharmacogenetic research and how this application may be brought from the "bench to the bedside."
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188382PMC
December 2011