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Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

RATIONALE: Whether biomarkers can be used to predict response to inhaled corticosteroids (ICS) or long-acting muscarinic antagonists (LAMA) in mild persistent asthma is unclear. OBJECTIVES: In a prespecified exploratory analysis of a randomized clinical trial of 295 participants 12 years of age or older with uncontrolled mild persistent asthma, we sought to identify biomarkers of treatment response after 12 weeks of ICS (mometasone, 200 μg or 220 μg twice/d), LAMA (tiotropium, 5 μg/d), or placebo in adults (⩾18 yr) and adolescents (12–17 yr) separately. METHODS: The primary outcome was a composite outcome of asthma control (treatment failure, asthma control days, and forced expiratory volume in 1 second [FEV(1)]). Analyses examined type 2 inflammatory biomarkers and physiologic biomarkers. We assessed the area under the receiver operating characteristic curve (AUC) for response to ICS and LAMA (each versus placebo). An AUC of 0.5 suggests no discrimination, 0.7–0.8 is considered acceptable, more than 0.8–0.9 is considered excellent, and more than 0.9 is considered outstanding. RESULTS: In 237 adults, sputum and blood eosinophil levels and fractional exhaled nitric oxide (Fe(NO)) each predicted ICS response (AUCs: 0.61 [95% confidence interval (CI), 0.53–0.69], 0.64 [95% CI, 0.56–0.72], and 0.62 [95% CI, 0.54–0.70], respectively; all P

Objective There is a high prevalence of obesity in people with asthma, and obesity is associated with poorly controlled asthma. Significant weight loss might improve asthma control: the purpose of this study was to investigate patient characteristics and factors that might affect implementation of a weight loss and/or roflumilast intervention, to target both obesity and asthma. Methods A cross‐sectional study of people with obesity and poorly controlled asthma performed at 13 sites across the United States. Results One hundred and two people participated in this study. Median BMI was 37 (IQR 35–42). The majority, 55%, were African American and 76% were female. Fifty two percent had very poorly controlled asthma. Most participants were quite sedentary (70% reported being inactive or participating only in light‐intensity activities according to the Stanford Brief Activity Survey). Participants reported significant impairments related to physical function on the Impact of Weight on Quality of Life‐Lite questionnaire (median score 67 [IQR 41–84]). Thirty‐five percent of participants reported mild, and 2 % moderate, depressive symptoms as assessed by the Patient Health Questionnaire‐9. Conclusions Poorly controlled asthma and obesity often affect minority populations and are associated with significant impairments in health related to physical function and low levels of physical activity that might complicate efforts to lose weight. Interventions targeted at poorly controlled asthma associated with obesity in the United States need to address factors complicating health in underserved communities, such as increasing opportunities for physical activity, while also managing activity limitations related to the combination of asthma and obesity.

BACKGROUND Research participants often misunderstand the required elements of informed consent information whether provided in written or oral format. Informed consent instruments with embedded evidence-based learning theory principles administered by multimedia electronic formats may improve comprehension and retention. OBJECTIVE The objective was to determine if study information comprehension and retention using an interactive multimedia video consent process was non-inferior to comprehension and retention after an in-person face-to-face interaction with a conventional written consent document for caregivers and adolescents enrolling in a clinical trial. METHODS Participants were caregivers and children aged 12- to-17 years who were considering enrollment in a clinical trial of asthma treatments. Consent information was presented as a multimedia web-based video consent interaction or as a conventional written consent document with in-person interaction between prospective participants and the study staff. The trial was a parallel nonrandomized non-inferiority design comparing the two consent methods. Caregivers and adolescents completed a 17-item open-ended comprehension questionnaire (score range, 17-51) at enrollment and end of study 20 weeks later. Comprehension and retention were compared between consent formats. Non-inferiority was established if the 95% Confidence Interval (CI) upper bound of the difference in scores (conventional format minus web-based) was less than the non-inferiority margin of 2.4; superiority was established if the upper bound of the CI was less than zero. RESULTS Fifty-four caregivers and adolescents dyads completed the interactive multimedia web-based video consent and 25 dyads completed the conventional consent. Thirty-three percent of all adolescents were Black, 57% were male, and 61% had a household income less than $60,000/year. For caregivers, the interactive multimedia web-based format was non-inferior to the conventional format at enrollment (mean [95% CI]) differerence between conventional and web-based, -0.30 (-2.52, 1.92) and and was superior at end of study 20 weeks later, -2.20 (-3.9, -0.5). There was a loss of comprehension over 20 weeks of -1.65 (-3.1, -0.19) with the conventional, but not the multimedia web-based format 0.14 (-0.84, 1.12). For adolescents, non-inferiority of the multimedia web-based format was not established. CONCLUSIONS Consent information delivered through an interactive multimedia web-based platform that incorporates evidence-based learning theory principles is understood as well as a conventional consent discussion in caregivers considering enrolling their adolescent in an asthma clinical trial. Retention of study information over time was better with a multimedia format in caregivers. CLINICALTRIAL ClinicalTrials.gov NCT02061280, NCT01437995

Rationale: For children with asthma, access to quick-relief medications is critical to minimizing morbidity and mortality. An innovative and practical approach to ensure access at school is to maintain a supply of stock albuterol that can be used by any student who experiences respiratory distress. To make this possible, state laws allowing for stock albuterol are needed to improve medication access. Objectives: To provide policy recommendations and outline steps for passing and implementing stock albuterol laws. Methods: We assembled a diverse stakeholder group and reviewed guidelines, literature, statutes, regulations, and implementation documents related to school-based medication access. Stakeholders were divided into two groups—legislation and implementation—on the basis of expertise. Each group met virtually to review documents and draft recommendations. Recommendations were compiled and revised in iterative remote meetings with all stakeholders. Main Results: We offer several recommendations for crafting state legislation and facilitating program implementation. 1) Create a coalition of stakeholders to champion legislation and implement stock albuterol programs. The coalition should include school administrators, school nurses and health personnel, parents, or caregivers of children with asthma, pediatric primary care and subspecialty providers (e.g., pulmonologists/allergists), pharmacists, health department staff, and local/regional/national advocacy organizations. 2) Legislative components critical for effective implementation of stock albuterol programs include specifying that medication can be administered in good faith to any child in respiratory distress, establishing training requirements for school staff, providing immunity from civil liability for staff and prescribers, ensuring pharmacy laws allow prescriptions to be dispensed to schools, and suggesting inhalers with valved holding chambers/spacers for administration. 3) Select an experienced and committed legislator to sponsor legislation and guide revisions as needed during passage and implementation. This person should be from the majority party and serve on the legislature’s health or education committee. 4) Develop plans to disseminate legislation and regulations/policies to affected groups, including school administrators, school nurses, pharmacists, emergency responders, and primary/subspecialty clinicians. Periodically evaluate implementation effectiveness and need for adjustments. Conclusions: Stock albuterol in schools is a safe, practical, and potentially life-saving option for children with asthma, whether asthma is diagnosed or undiagnosed, who lack access to their personal quick-relief medication. Legislation is imperative for aiding in the adoption and implementation of school stock albuterol policies, and key policy inclusions can lay the groundwork for success. Future work should focus on passing legislation in all states, implementing policy in schools, and evaluating the impact of such programs on academic and health outcomes.

Roughly 9% of African-Americans carry 1 copy of the sickle β-globin allele [sickle-cell trait (SCT)]. The sickle allele may affect the host responses in a way that protects against sequelae of malaria. Besides the association with sporadic episodes of erythrocyte sickling, acute chest syndrome, and sudden death, the SCT is generally regarded as asymptomatic. Separately, and for unclear reasons, the African-Americans have an elevated risk compared to whites for several immune-mediated diseases, including asthma, eczema, and other respiratory conditions. We propose to determine whether the SCT contributes to the elevated risk of these inflammatory conditions. We performed a retrospective cohort study of children with and without the sickle trait to assess the risk for common immune-mediated conditions. The cohorts were individually matched, and multiple logistic regression was used with variables selected using a backward stepwise approach. A second approach (case-control design) assessed the odds of the SCT among African-Americans with and without asthma. We found 2,481 children with and 4,962 matched patients without the SCT in the cohort design. The sickle trait was associated with greater odds for several immune-mediated conditions in a multivariable analysis, but not associated with asthma (odds ratio, OR=1.10

Asthma is difficult to diagnose in the child with sickle cell disease because symptoms and pulmonary function abnormalities are similar to the spectrum of pulmonary manifestations in sickle cell disease. There are no published reports of controlled trials of asthma medications in children with sickle cell disease. Thus, treatment decisions should be guided by the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf). However, issues specific to children with sickle cell disease should be considered. Initial strategies should focus on control of environmental triggers, as effectiveness on asthma outcomes is proven and the cost for implementation can be low. Use of short- and long-acting β2-agonists may prolong QTc, particularly in this population of children who already have a higher prevalence of prolonged QTc than the general population. Long-acting β2-agonist use has been associated with life-threatening asthma exacerbations with ...

OBJECTIVE: Asthma is a common chronic disease that disproportionately affects children and minorities, particularly African Americans. Inhaled bronchodilators are first-line treatment for asthma exacerbations, but individual bronchodilator response (BDR) varies by race and ethnicity. Studies have attempted to examine the genetic underpinnings of African American BDR, but many did not include young children and/or were not conducted when subjects were experiencing an actual asthma exacerbation. Therefore, this pilot study tested candidate single nucleotide polymorphisms’ (SNPs’) association with pediatric African American BDR during an acute asthma exacerbation. METHODS: This was a prospective study of pediatric asthma patients ages 2 – 18 years seeking care in the ED for an asthma exacerbation. We measured BDR before and after each inhaled bronchodilator treatment using both the Pediatric Asthma Severity Score (PASS) asthma severity score and spirometry, and divided patients’ BDR into equal terciles (low, medium, high). We collected genomic deoxyribonucleic acid (DNA) and examined whether 21 candidate SNPs from a review of the literature were associated with BDR using crude odds ratios and adjusted analysis (incorporating age, gender, obesity, and home tobacco smoke exposure). RESULTS: The final sample population was 53 children, with an average age of 7.2 years. The average initial PASS score (on a scale of ascending severity from 0–6) was 2.5 (standard deviation (SD) 1.6), and average initial forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) as a percent of predicted was 75.8% (SD 10.3%). After adjusting for body mass index (BMI), age category, gender, and smoke exposure, rs912142 was associated with decreased odds of having low BDR (odds ratio (OR) 0.20, 95% confidence interval (CI) 0.02–0.92), and rs7081864 and rs7903366 were associated with decreased odds of having high BDR (OR 0.097, 95% CI 0.009–0.62) CONCLUSIONS: In a study measuring BDR in African American children during an acute asthma exacerbation, we found 3 SNPs significantly associated with BDR that provide bidirectional information regarding a child’s potential response to emergency asthma exacerbation treatment. Once validated in larger studies and implemented into practice, such information could guide pharmacogenomic evidence-based emergency asthma treatment that improves patient outcomes.

The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene-drug pairs as "level A," for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)-affiliated health systems across the US. Inpatient and/or outpatient electronic-prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658-15,781) in 2011 to 17,335 (CI: 17,283-17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632-7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype-guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.

The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.

BACKGROUND: Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking. OBJECTIVE: To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down. METHODS: In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator). RESULTS: Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59–1.78] and 1.29 [95% CI, 0.65–2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers. CONCLUSIONS: In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.

Purpose of review Telemedicine, defined as synchronous video visits between a provider and a child with asthma, often takes place in the school setting. This review examines the new electronic sensors for adherence monitoring and studies that used telemedicine in the school setting to improve asthma outcomes. Recent findings School-based telemedicine provides an important service to families of school-aged children who have difficulty due to time and distance in planning and keeping in-person appointments with primary or specialty providers. Significant improvements in objective measures of asthma control are inconsistently observed although caregiver and parent quality of life and child self-management behaviors are improved and satisfaction is high. Assessment and outcomes related to adherence are mentioned in studies but results are not often reported. However, it appears that adherence interventions are beneficial while maintained but the effects are not sustained upon intervention discontinuation. Summary The school setting provides a convenient and suitable environment to conduct telemedicine visits between school-aged children and their primary care or specialty provider. Electronic adherence sensors allow review of controller and rescue medication use through a cloud-based dashboard and provides an opportunity for real-time assessment and intervention by providers to improve asthma outcomes.

Background Little is known about economic and productivity loss by severity of asthma. We investigate health-care utilization, direct medical costs, and indirect costs due to productivity loss from asthma by severity. Methods We conducted a cross-sectional analysis of the Medical Expenditure Panel Survey database (2010-2017) of patients with asthma aged ≥12 years and categorized them into mild, moderate, and severe asthma groups based on symptom control medications. Study outcomes included health-care utilization, direct medical costs, and indirect costs of asthma-related absenteeism. We used zero-inflated Poisson regression models to estimate incremental health-care utilization and generalized linear models to estimate incremental annual direct medical costs compared to patients without asthma. Results An estimated 139 million persons had an asthma diagnosis. Of patients with asthma, 77.1%, 22.2%, and 0.7% had mild, moderate, and severe asthma, respectively. Compared to patients without asthma, patients with asthma had incremental mean differences of 4.16 outpatient visits, 0.18 emergency department visits, and 0.07 hospitalizations per year. Annual direct medical costs were significantly associated with asthma severity ($3305 in mild, $7250 in moderate, and $9175 in severe asthma) (P < 0.05). Patients with mild, moderate, and severe asthma reported 0.76, 2.31, and 7.19 missed work or school days, resulting in $106, $321, and $1000 indirect costs per person per year, respectively. Conclusion Asthma-related direct and indirect costs are significantly associated with asthma severity, with severe asthma medical costs being about three times higher than mild. Controlling asthma symptoms is important to reduce the economic and social burden of asthma.

Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy number variation and 9 common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

BACKGROUND Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best‐worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx‐guided pharmacotherapy for antidepressant management.

BACKGROUND:In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS:In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (

Precision medicine is expected to impact the care of people with asthma, given its high disease prevalence, heterogeneity of pathophysiologic mechanisms, and consequent clinical phenotypes. A novel phenotype-stratified clinical trial conducted by the NHLBI AsthmaNet Consortium, titled Steroids in Eosinophil Negative Asthma (SIENA), was a randomized, multicenter, clinical trial that prospectively stratified individuals according to their baseline level of sputum inflammation during a screening period. Two phenotypic strata were assigned based on an a priori defined extent of sputum eosinophilia (Eos Low versus Eos High). This article describes: the scientific premise for the trial design, including assumptions used for power calculations; modifications to the analysis plan implemented after the trial started due to a higher than expected prevalence of one phenotypic stratum which impacted the ability to accrue sufficient subjects within the planned budget and study period; investigator alternatives to address the strata imbalance weighing scientific impact and study feasibility; and the final modified SIENA study design and analysis plan. SIENA was successfully completed in a manner that maintained meaningful outcomes. We conclude with recommendations for incorporation of pre-specified contingency plans into phenotype-directed protocols, to address the potential for differences in observed compared to estimated prevalence of different phenotypes in a study population. These approaches can be applied to precision medicine trials for the future.

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype‐guided pediatric dosing of PPI medications. Children aged 5–17 years old with gastric‐acid‐related conditions were randomized to receive either conventional dosing of a PPI or genotype‐guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype‐guided dosing arm (P

Nonadherence to asthma medications is prevalent among adolescents and young adults (AYAs) with asthma, leading to worsened control of asthma symptoms and more frequent exacerbations. AYAs have unique developmental transitional challenges that may alter medication adherence. We aimed to use a socio-ecological framework to explore the effect of transitional challenges from adolescence to young adulthood on asthma controller medication adherence and to identify possible strategies to promote medication adherence.We conducted qualitative semi-structured interviews by phone with 7 adolescents (14 to 17 years), their respective caregivers, and 7 young adults (18 to 30 years). Participants were recruited from a respiratory clinical trial network and pulmonary clinics in 4 states at 6 different sites through convenience sampling. Interviews were audio recorded, transcribed and coded using thematic analyses.Participants identified personal challenges affecting adherence to asthma medications during the transition from adolescence to young adulthood including responsibility for asthma self-management, understanding of asthma condition and severity, embarrassment, and life demands. Health systems factors including medication cost, challenges with insurance, difficulties obtaining refills, and difficulty with access to medications at school also impacted asthma medication adherence. Participants recommended adherence strategies including improved access to inhalers, incorporating asthma medications into daily routines, and using reminders.Focusing on the transitional challenges of AYAs during the time period from adolescence to young adulthood is necessary for supporting their asthma medication adherence and creating future interventions. Socio-ecological and systems factors should also be targeted for improved asthma medication adherence.Supplemental data for this article can be accessed online at https://doi.org/10.1080/02770903.2021.1897836.

* Abbreviations: FeNO — : fractional exhaled nitric oxide ICS — : inhaled corticosteroid LABA — : long-acting β2-agonist LAMA — : long-acting muscarinic antagonist SABA — : short-acting β2-agonist SCIT — : subcutaneous immunotherapy SLIT — : sublingual immunotherapy SMART — : single maintenance and reliever therapy The National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group (hereinafter “panel”) of the National Heart, Lung, and Blood Institute recently published its 2020 Focused Updates to the Asthma Management Guidelines (https://www.nhlbi.nih.gov/asthmaguidelines).1 These are the first updates from the panel since 2007, a remarkably long interval given the advances in care of the last decade. Using the Grading Recommendations, Assessment, Development, and Evaluation platform,2 the panel made 19 recommendations across six topic areas: intermittent inhaled corticosteroid (ICS) therapy, long-acting muscarinic antagonist (LAMA) therapy, indoor allergen-mitigation strategies, immunotherapy, fractional exhaled nitric oxide (FeNO) testing, and bronchial thermoplasty.3 Of these, 18 are relevant to children and adolescents (Table 1). The panel made strong recommendations (to be implemented by clinicians for almost all their patients as standard of care) and conditional recommendations (intended for many individuals as part of a shared decision-making process involving the clinician, family, and patient). For pediatric clinicians, the most exciting updates are those affirming several treatment options for using ICS with long-acting β2-agonists (LABAs) and LAMAs. Those for allergen mitigation, immunotherapy, and FeNO testing provide useful clarifications but not transformative alternatives for care. Of note, the updates did not address biological therapies because at the time that a decision regarding which topics to update was made (2014), only one biologic (omalizumab) was available. View this table: TABLE 1 New Recommendations of the 2020 Focused Updates by Age Group The updates’ most highly pediatric-relevant recommendations involve three treatment options: (1) intermittent ICS dosing with as-needed short-acting β2-agonist (SABA) for quick-relief therapy, (2) single maintenance and reliever … Address correspondence to Stephen J. Teach, MD, MPH, Children’s National Hospital, 111 Michigan Ave NW, Washington, DC 20010. E-mail: steach{at}childrensnational.org

Informed consent often fails to provide patients and families with a full understanding of the proposed procedure. We developed an informed consent checklist for identifying specific aspects of the surgical consent that were not fully understood by families. The purpose of this study was to measure the effect of using this checklist on families' knowledge, satisfaction, experience, and decisional conflict during the consent process. The families of pediatric patients scheduled for an orthopaedic preoperative visit were prospectively randomized into one of two groups: checklist or traditional appointment. Families in the checklist group completed the informed consent checklist which was then used by the surgeon to further discuss aspects of the surgery that needed clarification. Those in the traditional group had similar discussions about surgery without the aid of a checklist. Sixty-one families participated in the study; 27 in the checklist group and 34 in the traditional group without a checklist. The checklist group reported no difference in mean scores for all satisfaction (P = 0.37), decisional conflict (P = 0.51), and knowledge items (P = 0.31). For patient experience, the traditional group reported the visits were significantly more relaxed (mean 4.9, 95% confidence interval (CI) 4.8-5.0) than the checklist group (mean 4.5, 95% CI 4.3-4.7). Our results suggest that having a family member complete the informed consent checklist prior to meeting with the surgeon did not improve, and may worsen, the consent experience for some families. Other methods need to be evaluated to determine the optimal consent process from the family's perspective.

Asthma guidelines provide clinicians with evidence-based management strategies for this chronic condition. The preferred therapy for patient with persistent asthma is inhaled corticosteroids. However, ∼40% of the patients with persistent asthma continue to present with symptoms while treated according to the guidelines. Multiple factors are being explored to explain the variability in response to inhaled corticosteroids including asthma phenotype and genetic predisposition among others. The nonatopic asthma phenotype has been described in the literature. These patients tend to have milder symptoms of asthma and typically outgrow their asthma by adolescence. They present with chronic asthma symptoms in the absence of a positive allergy test, either skin prick test or specific immunoglobulin E blood test. Although patients with nonatopic asthma share many characteristics with patients with atopic asthma, there are several studies that suggest a different inflammatory pathway may be involved in their pathophysiology. Therefore, it is possible that children with nonatopic asthma could respond differently to inhaled corticosteroids compared with those with atopic asthma. Currently there is a variable definition of this phenotype. Furthermore, there is a paucity of therapeutic trial directed toward the patients with nonatopic asthma specifically. Future research should be guided toward identifying the inflammatory pathways in nonatopic asthma and potential phenotype-guided therapies.

This cross-sectional study assesses potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence and estimating the prevalence of potentially actionable prescribing decisions., Key Points Question What is the opportunity for genotype-guided prescribing among pediatric patients in the US? Findings In this serial cross-sectional study of annual prescribing data at 16 health systems representing approximately 2.9 million pediatric patients per year from 2011 to 2017, the annual prevalence of exposure to at least 1 Clinical Pharmacogenetics Implementation Consortium level A drug ranged from 7987 to 10 629 per 100 000 pediatric patients, with increasing prevalence before reaching a plateau in 2014. The medications with the highest potential for actionability were analgesics (oxycodone, codeine, and tramadol), the antiemetic ondansetron, and antidepressants (citalopram, escitalopram, and amitriptyline). Meaning These findings suggest that ample opportunity exists for genotype-guided prescribing among pediatric patients in the US, especially for drugs metabolized by CYP2D6 or CYP2C19., Importance Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. Objective To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. Design, Setting, and Participants This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children’s hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Exposures Prescription of 38 level A medications based on electronic health records. Main Outcomes and Measures Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Results Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. Conclusions and Relevance These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.

OBJECTIVES: The emergency department (ED) is a challenging setting to conduct pharmacogenomic studies and integrate that data into fast-paced and potentially life-saving treatment decisions. Therefore our objective is to present the methods and feasibility of a pilot pharmacogenomic study set in the ED that measured pediatric bronchodilator response (BDR) during acute asthma exacerbations. METHODS: This is an exploratory pilot study that collected buccal swabs for DNA and measured bronchodilator response during ED encounters for pediatric asthma exacerbations. We evaluated the study’s feasibility with a qualitative analysis of ED provider surveys and quantitatively by the proportion of eligible patients enrolled. RESULTS: We enrolled 59 out of 90 patients (65%) that were identified and considered eligible during a 5-month period (target enrollment 60 patients over 12 months). The median patient age was 7 years (interquartile range 4–9 years), 61% (N=36) were male, and 92% (N=54) were African American. Quality DNA collection was successful for all 59 patients. ED provider survey response rate was 100%. Most ED providers reported the study did not impact their workflow (98% of physicians, 88% of nurses, and 90% of respiratory therapists). ED providers did report difficulties with spirometry in the younger age group. CONCLUSIONS: Pharmacogenomic studies can be conducted in the ED setting, and enroll a younger patient population with a high proportion of minority participants. By disseminating this study’s methods and feasibility analysis, we aim to increase interest in pharmacogenomic studies set in the ED and aimed towards future ED-based pharmacogenomic decision-making.

Background Translating pharmacogenetic research findings that have shown clinical efficacy into sustainable, routine clinical care at the institutional level requires strong evidence of improved patient outcomes bolstered by equitable reimbursement and a sound financial analysis. Although extensive research on the clinical value of pharmacogenetics has been completed, adoption into clinical practice lags due to a lack of evidence of clinical effectiveness and limited reimbursement. Methods The Sustainability Working Group within the NHGRI IGNITE I Network conducted an online survey of funded and non-funded IGNITE members to determine which genes they are researching, which have been translated into clinical practice, and how tests are billed. Data from the online surveys was consolidated and analyzed with results being tabulated for key findings. Due to the limited sample size, statistical analysis was forgone and results should be considered directional in nature. Results Fifteen out of twenty (75%) online survey responses were received and analyzed from IGNITE member sites delivering clinical care. Forty different genes were identified as being used for either research or clinical care. Thirty-two different genes were reported as being used clinically, an average of 6.9 genes were reported per site. Twenty-two and twenty-one genes were reported as being billed to third party payers or patients respectively. Although the survey did not ask whether sites submitting for reimbursement received payment, Medicare and Medicaid only reimburse for 6 of the 40 (15%) genes being tested. Of the 40 genes, 18 are rated by CPIC as having A/B level of evidence with the remainder being rated as C/D or having no rating. Approximately 32% more A/B rated genes were being reported clinically than non-A/B. Conclusion Adoption of pharmacogenetic testing continues to lag even at sites where leading experts conduct research and have the capability to report tests clinically. Clinical research that supports CPIC A level of evidence is important for provider and payer support. Adoption of pharmacogentic testing must also be justified financially, reimbursement is one key factor, and more health economic studies are needed in order to capture the value created by preventing drug-gene adverse events, emergency room visits, and hospitalizations.

Increasing enthusiasm for clinical pharmacogenetic testing and the availability of pharmacogenetic-based guidelines indicate that pediatricians will increasingly be expected to interpret and apply pharmacogenetic test results into medical care. Previous studies have identified a lack of knowledge on pharmacogenetics across many physician specialties; however, this has not been systematically assessed among pediatricians. To evaluate pediatrician knowledge, attitude, and educational interest in pharmacogenetics, we surveyed physician cohorts from both the United States (U.S.) and Japan. A total of 282 pediatricians (210 from the U.S. and 72 from Japan) participated in an anonymous survey (online or hardcopy) on pharmacogenetics knowledge, perception, and education. Over 50% of all respondents had >10 years of clinical experience and >75% had some prior education in genetics. However, 80% of all respondents indicated that implementation of clinical pharmacogenetic testing will improve efficacy and safety, and that pediatricians should be capable of applying this testing to their practice. Moreover, the majority (83.1%) were interested in educational opportunities on pharmacogenetics, particularly on result interpretation and therapeutic recommendations. Taken together, these data indicate that although practical knowledge of pharmacogenetics among pediatricians in the U.S. and Japan is currently very low, their interest in clinical pharmacogenetics and related education is high, which will likely facilitate future implementation.

This was a randomized controlled trial of low thermal damage device versus traditional electrosurgery in children 3 to 17 years old with a clinical diagnosis of sleep disordered breathing, obstructive sleep apnea with adenotonsillar hypertrophy, or recurrent adenotonsillitis. Pain score (Wong-Baker FACES pain scale) was recorded each morning before eating, drinking, or administering pain medication for 14 days postoperatively. Seventy-five children were enrolled. There was no difference in the rate of decrease in pain scores. A significant interaction between rate of pain decrease and number of pain medication doses was present ( P < .0001). Median number of pain medication doses was greater with electrosurgery (36, range: 7-49) versus low thermal device (21, range: 2-124; P = .001). Pain scores reached 0 after a median of 7 days (95% confidence interval [CI], 5.2-8.6) for low thermal device and 9 days (95% CI, 8.0-10.0) for electrosurgery ( P = .67). One child randomized to electrosurgery was withdrawn due to hospitalization for postoperative bleed. In children, low thermal device results in significantly less pain medication used during the postoperative period than electrosurgery.

The National Asthma Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma will update the guidelines on 6 topic areas. This review summarizes the findings for the charge to assess effectiveness of intermittent inhaled corticosteroid therapy with and without long-acting beta-agonist therapy in children 0 to 4 years of age, and children and adults 5 years and older. The complete report can be found on the Agency for Healthcare Research and Quality website.

A growing body of literature has investigated optimizing asthma management by identifying phenotypes and biomarkers to guide the treatment. In particular, management of asthma in preschool children remains challenging due to different phenotype presentation in early life. The focus of this review is to summarize the recent data on personalized medicine in management of preschool children with wheezing.

Asthma causes enormous suffering and cost for children in the US and around the world [ [1] , [2] , [3] ]. Co-morbid gastroesophageal reflux disease (GERD) makes asthma management more difficult due to increased symptoms. Proton pump inhibitor (PPI) drugs are effective at improving to GERD symptoms, however they have demonstrated only modest and variable effects on asthma control in the setting of co-morbid GERD. Importantly, PPI metabolism and efficacy depend on CYP2C19 genotype. The Genotype Tailored Treatment of Symptomatic Acid Reflux in Children with Uncontrolled Asthma (GenARA) study is a randomized, double-blind, placebo-controlled trial to determine if genotype-tailored PPI dosing improves asthma symptoms among children with inadequately controlled asthma and GERD symptoms. This study has an innovative design to both assess the efficacy of genotype-tailored PPI dosing and perform pharmacokinetic modeling of the oral PPI Lansoprazole. Children ages 6–17 years old with clinician-diagnosed asthma and mild GERD symptoms will submit a saliva sample for CYP2C19 genotyping. Participants will undergo a two-step randomization to: (1) genotype-tailored versus conventional dosing of open-label oral lansoprazole for pharmacokinetic modeling, and (2) genotype-tailored lansoprazole daily versus placebo for 24 weeks to determine the effect of genotype-tailored PPI dosing on asthma control. Measures of asthma control, spirometry, and nasal washes during acute illnesses will be collected at 8-week intervals throughout the study. GenARA will better define the effects of CYP2C19 genotype on the dose response of lansoprazole in children and adolescents and assess if a novel dosing regimen improves GERD and asthma control.

Background Pediatric asthma exacerbations are a frequent reason for emergency care. Early administration of oral systemic corticosteroids (OCS) in the emergency department (ED) decreases hospitalization rates and ED length-of-stay (LOS). However, it is unknown whether even earlier OCS administration by emergency medical services (EMS) in the prehospital setting further improves outcomes. Purpose To describe the background and methods of a type 1 hybrid effectiveness-implementation trial of EMS-administered OCS for pediatric asthma patients incorporating a stepped wedge design and the RE-AIM framework. Methods The study employs a non-randomized stepped wedge design where multiple EMS agencies adopt OCS as a treatment for pediatric asthma exacerbations at varying times. This design accommodates ethical considerations of studying pediatric subjects in the prehospital setting where informed consent is not feasible. We will compare hospitalization rates, ED LOS, and short-term healthcare costs between pediatric asthma patients who do and do not receive OCS from EMS. Using geographic information systems (GIS), we will measure how differences in outcomes scale with increasing EMS transport time. We will use the RE-AIM framework to guide a mixed methods analysis of barriers and enablers to EMS administration of OCS for pediatric asthma patients, including quantitative measures of adoption and uptake and qualitative EMS provider focus group data. Conclusion This trial will determine if earlier EMS administration of OCS to pediatric asthma patients decreases hospitalizations, ED LOS, and short-term healthcare costs, and if those outcomes scale with longer EMS transport times. We will identify barriers and enablers to implementing EMS-administered OCS for pediatric asthma patients.