Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

RUNX1 Isoforms Regulate RUNX1 and Target-Genes Differentially in Platelets-Megakaryocytes: Association with Clinical Cardiovascular Events.

Background: Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoter to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream-gene regulation in megakaryocytes and platelets are unknown. Objectives: To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms. Methods: We performed studies on RUNX1 isoforms in megakaryocytic HEL cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD). Results: In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes (MYL9, F13A1, PCTP, PDE5A and others) differentially in HEL cells. In platelets RUNX1B transcripts (by RNAseq) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with F13A1, PCTP, PDE5A, RAB1B, and others, and negatively with MYL9. In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets F13A1 and RAB31 associated with acute events. Conclusions: RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner and this associates with acute events in CVD.

Youth Suicide and Preceding Mental Health Diagnosis.

Importance: Suicide is a leading cause of death among US youths, and mental health disorders are a known factor associated with increased suicide risk. Knowledge about potential sociodemographic differences in documented mental health diagnoses may guide prevention efforts. Objective: To examine the association of documented mental health diagnosis with (1) sociodemographic and clinical characteristics, (2) precipitating circumstances, and (3) mechanism among youth suicide decedents. Design, Setting, and Participants: This retrospective, cross-sectional study of youth suicide decedents aged 10 to 24 years used data from the Centers for Disease Control and Prevention National Violent Death Reporting System from 2010 to 2021. Data analysis was conducted from January to November 2023. Exposures: Sociodemographic characteristics, clinical characteristics, precipitating circumstances, and suicide mechanism. Main Outcomes and Measures: The primary outcome was previously documented presence of a mental health diagnosis. Associations were evaluated by multivariable logistic regression. Results: Among 40 618 youth suicide decedents (23 602 aged 20 to 24 years [58.1%]; 32 167 male [79.2%]; 1190 American Indian or Alaska Native [2.9%]; 1680 Asian, Native Hawaiian, or Other Pacific Islander [4.2%]; 5118 Black [12.7%]; 5334 Hispanic [13.2%]; 35 034 non-Hispanic; 30 756 White [76.1%]), 16 426 (40.4%) had a documented mental health diagnosis and 19 027 (46.8%) died by firearms. The adjusted odds of having a mental health diagnosis were lower among youths who were American Indian or Alaska Native (adjusted odds ratio [aOR], 0.45; 95% CI, 0.39-0.51); Asian, Native Hawaiian, or Other Pacific Islander (aOR, 0.58; 95% CI, 0.52-0.64); and Black (aOR, 0.62; 95% CI, 0.58-0.66) compared with White youths; lower among Hispanic youths (aOR, 0.76; 95% CI, 0.72-0.82) compared with non-Hispanic youths; lower among youths aged 10 to 14 years (aOR, 0.70; 95% CI, 0.65-0.76) compared with youths aged 20 to 24 years; and higher for females (aOR, 1.64; 95% CI, 1.56-1.73) than males. A mental health diagnosis was documented for 6308 of 19 027 youths who died by firearms (33.2%); 1691 of 2743 youths who died by poisonings (61.6%); 7017 of 15 331 youths who died by hanging, strangulation, or suffocation (45.8%); and 1407 of 3181 youths who died by other mechanisms (44.2%). Compared with firearm suicides, the adjusted odds of having a documented mental health diagnosis were higher for suicides by poisoning (aOR, 1.70; 95% CI, 1.62-1.78); hanging, strangulation, and suffocation (aOR, 2.78; 95% CI, 2.55-3.03); and other mechanisms (aOR, 1.59; 95% CI, 1.47-1.72). Conclusions and Relevance: In this cross-sectional study, 3 of 5 youth suicide decedents did not have a documented preceding mental health diagnosis; the odds of having a mental health diagnosis were lower among racially and ethnically minoritized youths than White youths and among firearm suicides compared with other mechanisms. These findings underscore the need for equitable identification of mental health needs and universal lethal means counseling as strategies to prevent youth suicide.

Obesity is associated with increased pediatric dengue virus infection and disease: A 9-year cohort study in Managua, Nicaragua.

BACKGROUND: Obesity is on the rise globally in adults and children, including in tropical areas where diseases such as dengue have a substantial burden, particularly in children. Obesity impacts the risk of severe dengue disease; however, the impact on dengue virus (DENV) infection and dengue cases remains an open question. METHODS: We used 9 years of data from 5,940 children in the Pediatric Dengue Cohort Study in Nicaragua to examine whether pediatric obesity is associated with increased susceptibility to DENV infection and symptomatic presentation. Analysis was performed using Generalized Estimating Equations adjusted for age, sex, and pre-infection DENV antibody titers. RESULTS: From 2011 to 2019, children contributed 26,273 person-years of observation, and we observed an increase in the prevalence of overweight (from 12% to 17%) and obesity (from 7% to 13%). There were 1,682 DENV infections and 476 dengue cases in the study population. Compared to participants with normal weight, participants with obesity had higher odds of DENV infection (Adjusted Odds Ratio [aOR] 1.21, 95% confidence interval [CI] 1.03-1.42) and higher odds of dengue disease given infection (aOR 1.59, 95% CI 1.15-2.19). Children with obesity infected with DENV showed increased odds of presenting fever (aOR 1.46, 95% CI 1.05-2.02), headache (aOR 1.51, 95% CI 1.07-2.14), and rash (aOR 2.26, 95% CI 1.49-3.44) when compared with children with normal weight. CONCLUSIONS: Our results indicate that obesity is associated with increased susceptibility to DENV infection and dengue cases in children, independently of age, sex, and pre-infection DENV antibody titers.

Congruency of Crash- and Hospital- Reported Injuries Among Child Passengers.

INTRODUCTION: Prior work has found incongruencies in injury information reported by crash and hospital records. However, no work has focused on child passengers. The objective of this study was to compare crash scene and hospital-reported injury information for crash-involved child passengers. This study also explored injury location and severity by child age and restraint type. METHODS: Utilizing linked New Jersey data from 2017 through 2019, the authors identified crash-involved child passengers <13 years old and their injuries in crash and hospital reports. Then, they characterized the congruency of injury frequency, severity, and location, as well as the frequency of injuries by child age and restraint type. Analyses were conducted from December 2023 through February 2024. RESULTS: Of 84,060 crash-involved child passengers, crash reports documented 7,858 (9%) children with at least "possible" injuries, while 2,577 (3%) had at least one injury in hospital events. Crash report and hospital data were incongruent for both body region of injury and injury severity. The proportion of children injured increased as children's ages increased and as restraint type progressed. CONCLUSIONS: Crash reports overestimated the number of injured child passengers and misrepresented injury severity and locations. Child restraint systems mitigated a child's injury risk. Importantly, injury information documented on crash reports currently informs the allocation of traffic safety resources. These results highlight the importance of improving these reports' accuracy and underscore calls to link administrative datasets for public health efforts.

Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Preparing to "Live a Life of Possibilities": Experiences of Healthcare Providers Readying Autistic Adolescents and Their Families for Independent Driving.

Autistic adolescents and their families may experience barriers to transportation, including independent driving, which is critical to supporting quality of life and engagement in social, educational, and employment opportunities. Healthcare providers may feel unprepared to provide guidance to autistic adolescents, although they are among the professionals families turn to for guidance. This study describes providers' experiences supporting autistic adolescents and families in the decision to pursue licensure and identifies barriers experienced in providing support. We conducted interviews with 15 healthcare providers focused on how they support autistic adolescents and their families in navigating topics related to independence, driving, and transportation. Key themes identified included: importance of understanding adolescents' perspectives and motivations, approaches to readying caregivers for children to pursue driving, and role of providers in fostering agreement between adolescents and caregivers. Results reflect healthcare providers as intermediaries between autistic adolescents and caregivers making the decision to pursue licensure and bring families to consensus. Our findings emphasize the importance of healthcare providers, in collaboration with community-based providers, in supporting autistic adolescents and their families considering licensure. Improving conversations between providers and families provides opportunity to better support quality of life among autistic adolescents and their caregivers navigating the transition to independence.

Obesity is associated with increased pediatric dengue virus infection and disease: A 9-year cohort study in Managua, Nicaragua.

Background: Obesity is on the rise globally in adults and children, including in tropical areas where diseases such as dengue have a substantial burden, particularly in children. Obesity impacts the risk of severe dengue disease; however, the impact on dengue virus (DENV) infection and dengue cases remains an open question. Methods: We used 9 years of data from 5,940 children in the Pediatric Dengue Cohort Study in Nicaragua to examine whether pediatric obesity is associated with increased susceptibility to DENV infection and symptomatic presentation. Analysis was performed using Generalized Estimating Equations adjusted for age, sex, and pre-infection DENV antibody titers. Results: From 2011 to 2019, children contributed 26,273 person-years of observation, and we observed an increase in the prevalence of overweight (from 12% to 17%) and obesity (from 7% to 13%). There were 1,682 DENV infections and 476 dengue cases in the study population. Compared to participants with normal weight, participants with obesity had higher odds of DENV infection (Adjusted Odds Ratio [aOR] 1.21, 95% confidence interval [CI] 1.03-1.42) and higher odds of dengue disease given infection (aOR 1.59, 95% CI 1.15-2.19). Children with obesity infected with DENV showed increased odds of presenting fever (aOR 1.46, 95% CI 1.05-2.02), headache (aOR 1.51, 95% CI 1.07-2.14), and rash (aOR 2.26, 95% CI 1.49-3.44) when compared with children with normal weight. Conclusions: Our results indicate that obesity is associated with increased susceptibility to DENV infection and dengue cases in children, independently of age, sex, and pre-infection DENV antibody titers.

Early reduction in cardiorespiratory fitness and diastolic reserve following radiation therapy for lung cancer.

BACKGROUND: Contemporary radiotherapy for the treatment of lung cancer is effective in targeting tumor tissue while limiting heart exposure, yet cardiac toxicity still occurs, often becoming clinically apparent years later. Cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular, cancer-related, and overall mortality and may serve as a sensitive measure of subclinical cardiac toxicity following anti-cancer treatments. Prior work has demonstrated a significant relationship between reduced CRF and impaired left-ventricular (LV) diastolic reserve in cancer survivors following thoracic radiotherapy. The purpose of this study was to assess early longitudinal changes in CRF and cardiac function in patients with lung cancer following radiotherapy. METHODS: Ten patients (69 [61-76] years, 70% female) with lung cancer without known cardiovascular disease scheduled to receive radiotherapy involving a clinically-relevant heart dose (≥ 5 Gy to > 10% of heart volume) were evaluated prior to and following treatment. Changes in CRF (peak oxygen consumption [VO2peak], oxygen uptake efficiency slope [OUES]), cardiac function (LV ejection fraction [LVEF], rest and exercise diastolic function [diastolic functional reserve index (DFRI)]), cardiac biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein [hsCRP]), and health-related quality of life (HRQOL; Functional Assessment of Cancer Therapy-General-7 [FACT-G7]) were measured. RESULTS: The VO2peak was reduced at baseline (1.245 [0.882-1.605] L·min- 1; 70 [62-86] %-predicted) and significantly declined (1.095 [0.810-1.448] L·min- 1, P = 0.047; 62 [56-76] %-predicted, P = 0.005) at 6.0 [3.0-6.0] months post-radiotherapy. Similarly, a significant decline in the OUES was observed (1.63 [1.27-1.88] to 1.57 [1.12-1.75], P = 0.032). Systolic cardiac function was normal at baseline and did not change following radiotherapy (LVEF; 62 [56-65]% to 66 [57-68]%, P = 0.475). The DFRI significantly declined following radiotherapy (34.9 [22.7-41.6] vs. 12.8 [3.1-35.9]). The hsCRP increased significantly from 4.4 [1.4-5.8] to 6.1 [3.7-20.7] g/L, P = 0.047 with a trend towards higher levels of NT-proBNP (65 [49-125] to 121 [88-191] pg/mL, P = 0.110). Health-related quality of life significantly decreased (FACT-G7; 21.5 [18.8-25] to 15.5 [11.5-20]; P = 0.021) post-radiotherapy. CONCLUSIONS: Patients with lung cancer receiving radiotherapy with a clinically-significant heart dose experience reductions in CRF (VO2peak, OUES) as early as six months following treatment with concurrent reductions in diastolic reserve (DFRI), HRQOL, and increases in cardiac biomarkers (NT-proBNP, hsCRP).

Caregivers' Perspectives on Use of and Need for Driving Resources for Their Autistic Adolescent.

Introduction: Autistic individuals who independently travel-or commute without companionship or supervision-report feeling more connected to social, education, and employment opportunities. Despite the potential for independent transportation to improve quality of life, little is known about what transportation-related resources, specifically driving focused ones, exist for autistic individuals or how they and their families find and use them. The objectives of this study were to characterize: (1) where and how families in the United States find driving-related resources for their autistic adolescents; (2) families' perceived availability and utility of identified resources; and (3) resources families believe should be developed. Methods: We conducted semi-structured interviews with 33 caregivers of autistic adolescents aged 16-24 years without an intellectual disability. We used a directed-content approach to develop and implement codes; three trained coders analyzed all transcripts (inter-rater reliability ≥0.8 for all codes). Members of the research team reviewed coded data and created code summaries, which were then developed and discussed by the larger research team to determine final consensus. Results: Caregivers described a few existing resources that were helpful in guiding driving-related decisions. In addition, caregivers voiced that there were limited resources tailored to the unique needs that arise while teaching or learning how to drive, particularly ones that support their own and their adolescent's mental health. The limited resources and services identified as helpful-specifically support groups/perspectives of other families and specialized driving instructors-are seemingly difficult to find, costly, and/or perceived as having geographic- and time-related barriers. Conclusion: There is a critical need and opportunity for stakeholders of the autism community to both expand access to existing and develop novel driving-related resources for families with autistic adolescents, with a particular focus of supporting caregiver and adolescent mental health.

Why is this an important issue?: Many autistic teens and young adults rely on caregivers, siblings, family, and friends to give them rides to the places they need to go. Research has found that resources and services created specifically for autistic people can help them decide whether driving is right for them, and if so, then learn how to drive. However, little is known about if, and if so how, families find or use these resources and services. What was the purpose of this study?: This study had three goals: (1) learn what driving resources and services autistic teens and young adults (and their families) use, (2) learn how they find these resources and services, and (3) learn what other things they think would help them make decisions about driving and learn how to drive. What did the researchers do?: The researchers asked 33 caregivers of autistic teens and young adults without an intellectual disability (ID) (teens and young adults were 16­24 years old) questions about their experiences finding and using driving resources and services. These conversations were recorded and later typed out word for word. What were the results of the study?: Caregivers said that they spend a lot of time looking for driving resources and services for their autistic teen or young adult. Many resources and services were not easy to use or helpful. Caregivers said that behind-the-wheel driving instructors with specific training teaching autistic individuals were the most helpful and/or wanted resource. However, caregivers also said that these instructors and their services were hard to find, cost a lot of money, and require families to spend a lot of time training with them to get results. In the future, caregivers said that making it easier to find and get driving resources and services (e.g., making them less expensive) was necessary. Caregivers also had strong interest in their family participating in support groups related to driving. What do these findings add to what was already known?: Previous research has shown that training, resources, and services designed specifically for autistic people help prepare autistic teens and young adults to drive. Before our study, it was unclear if, and if so how, families actually use these resources and services in the real world, or outside of academic research. Families in our study said that it is hard to find or get access to driving resources and services, especially those created specifically for autistic populations. This difficulty is one reason why families think it is stressful and hard for autistic teens and young adults to learn how to drive. What are the potential weaknesses in the study?: We only asked caregivers who lived in the Northeast part of the United States questions, so our findings may not be true for all families. Also, this study only asked questions to caregivers of autistic teens and young adults who did not have an ID. How will these findings help autistic adults now or in the future?: Our findings can help autistic teens and young adults by showing what resources and services families use and want to use while they are learning how to drive or making decisions about if driving is right for them.