Deep sequencing of candidate genes identified 14 variants associated with smoking abstinence in an ethnically diverse sample.

Despite the large public health toll of smoking, genetic studies of smoking cessation have been limited with few discoveries of risk or protective loci. We investigated common and rare variant associations with success in quitting smoking using a cohort from 8 randomized controlled trials involving 2231 participants and a total of 10,020 common and 24,147 rare variants. We identified 14 novel markers including 6 mapping to genes previously related to psychiatric and substance use disorders, 4 of which were protective (CYP2B6 (rs1175607105), HTR3B (rs1413172952; rs1204720503), rs80210037 on chr15), and 2 of which were associated with reduced cessation (PARP15 (rs2173763), SCL18A2 (rs363222)). The others mapped to areas associated with cancer including FOXP1 (rs1288980) and ZEB1 (rs7349). Network analysis identified significant canonical pathways for the serotonin receptor signaling pathway, nicotine and bupropion metabolism, and several related to tumor suppression. Two novel markers (rs6749438; rs6718083) on chr2 are flanked by genes associated with regulation of bodyweight. The identification of novel loci in this study can provide new targets of pharmacotherapy and inform efforts to develop personalized treatments based on genetic profiles.

Development of the data registry for the Cardiac Neurodevelopmental Outcome Collaborative.

Children with congenital heart disease (CHD) can face neurodevelopmental, psychological, and behavioural difficulties beginning in infancy and continuing through adulthood. Despite overall improvements in medical care and a growing focus on neurodevelopmental screening and evaluation in recent years, neurodevelopmental disabilities, delays, and deficits remain a concern. The Cardiac Neurodevelopmental Outcome Collaborative was founded in 2016 with the goal of improving neurodevelopmental outcomes for individuals with CHD and pediatric heart disease. This paper describes the establishment of a centralised clinical data registry to standardize data collection across member institutions of the Cardiac Neurodevelopmental Outcome Collaborative. The goal of this registry is to foster collaboration for large, multi-centre research and quality improvement initiatives that will benefit individuals and families with CHD and improve their quality of life. We describe the components of the registry, initial research projects proposed using data from the registry, and lessons learned in the development of the registry.

Predictive value of General Movements Assessment for developmental delay at 18 months in children with complex congenital heart disease.

BACKGROUND: Infants with complex congenital heart disease are at increased risk of impaired fetal brain growth, brain injury, and developmental impairments. The General Movement Assessment (GMA) is a valid and reliable tool to predict cerebral palsy (CP), especially in preterm infants. Predictive properties of the GMA in infants with complex congenital heart disease (CCHD) are unknown. AIM: To evaluate predictive properties of the GMA to predict developmental outcomes, including cerebral palsy (CP), at 18-months corrected age (CA) in children with CCHD undergoing heart surgery in the first month of life. METHODS: A prospective cohort of 56 infants with CCHD (35 males, 21 females) was assessed with GMA at writhing age (0-6 weeks CA) and fidgety age (7-17 weeks CA) and the Bayley Scales of Infant Development at 18 months. GMA focused on markedly reduced GM-variation and complexity (definitely abnormal (DA) GM-complexity) and fidgety movements. Predictive values of GMA for specific cognitive, language and motor delay (composite scores <85th percentile) and general developmental delay (delay in all domains) were calculated at 18 months. RESULTS: At fidgety age, all infants had fidgety movements and no child was diagnosed with CP. DA GM-complexity at fidgety age predicted general developmental delay at 18 months (71 % sensitivity, 90 % specificity), but predicted specific developmental delay less robustly. DA GM-complexity at writhing age did not predict developmental delay, nor did it improve prediction based on DA GM-complexity at fidgety age. CONCLUSIONS: In infants with CCHD and fidgety movements, DA GM-complexity at fidgety age predicted general developmental delay.

The use of biomarkers to guide precision treatment for tobacco use.

This review summarizes the evidence to date on the development of biomarkers for personalizing the pharmacological treatment of combustible tobacco use. First, the latest evidence on FDA-approved medications is considered, demonstrating that, while these medications offer real benefits, they do not contribute to smoking cessation in approximately two-thirds of cases. Second, the case for using biomarkers to guide tobacco treatment is made based on the potential to increase medication effectiveness and uptake and reduce side effects. Next, the FDA framework of biomarker development is presented along with the state of science on biomarkers for tobacco treatment, including a review of the nicotine metabolite ratio, electroencephalographic event-related potentials, and other biomarkers utilized for risk feedback. We conclude with a discussion of the challenges and opportunities for the translation of biomarkers to guide tobacco treatment and propose priorities for future research.

Developmental care pathway for hospitalised infants with CHD: on behalf of the Cardiac Newborn Neuroprotective Network, a Special Interest Group of the Cardiac Neurodevelopmental Outcome Collaborative.

Infants and children born with CHD are at significant risk for neurodevelopmental delays and abnormalities. Individualised developmental care is widely recognised as best practice to support early neurodevelopment for medically fragile infants born premature or requiring surgical intervention after birth. However, wide variability in clinical practice is consistently demonstrated in units caring for infants with CHD. The Cardiac Newborn Neuroprotective Network, a Special Interest Group of the Cardiac Neurodevelopmental Outcome Collaborative, formed a working group of experts to create an evidence-based developmental care pathway to guide clinical practice in hospital settings caring for infants with CHD. The clinical pathway, "Developmental Care Pathway for Hospitalized Infants with Congenital Heart Disease," includes recommendations for standardised developmental assessment, parent mental health screening, and the implementation of a daily developmental care bundle, which incorporates individualised assessments and interventions tailored to meet the needs of this unique infant population and their families. Hospitals caring for infants with CHD are encouraged to adopt this developmental care pathway and track metrics and outcomes using a quality improvement framework.

Motor development in infants with complex congenital heart disease: A longitudinal study.

AIM: To evaluate whether infants with complex congenital heart disease (CCHD) have an increased risk of impaired quality of motor behavior and delayed motor milestones. METHOD: A cohort of 69 infants with CCHD (43 males, 26 females) were assessed with the Infant Motor Profile (IMP) at three time periods between 6 to 18 months, mean ages in months (SD): 6.4 (0.7); 12.7 (1.0); 18.5 (0.7) IMP data were available from a reference sample of 300 Dutch infants. Analyses included multivariable logistic regression analysis to estimate differences in IMP scores below the 15th centile between children with CCHD and the reference group, and linear mixed-effects models to assess the effect of ventricular physiology and systemic oxygen saturation (SpO2) of less than 90% on IMP outcomes. RESULTS: Infants with CCHD had increased risks of total IMP scores below the 15th centile (lowest odds ratio [OR] at 18mo: 6.82 [95% confidence interval {CI} 2.87-16.19]), especially because of lower scores in the domains of variation, adaptability, and performance. Children with single ventricle CCHD scored consistently 3.03% (95% CI 1.00-5.07) lower than those with two ventricle physiology, mainly from contributions of the variation and performance domains. SpO2 of less than 90% was associated with 2.52% (95% CI 0.49-4.54) lower IMP scores. INTERPRETATION: CCHD, especially single ventricle physiology, increases risk of impaired motor development. WHAT THIS PAPER ADDS: Complex congenital heart disease (CCHD) substantially increases risk of impaired motor development. CCHD is associated with motor delay and reduced motor variation and adaptability. Single ventricle physiology increases the risk of impaired motor behavior.

Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial.

BACKGROUND: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown. METHODS: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes. RESULTS: A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P<0.001). CONCLUSIONS: Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.).

Modeling single-cell phenotypes links yeast stress acclimation to transcriptional repression and pre-stress cellular states.

Stress defense and cell growth are inversely related in bulk culture analyses; however, these studies miss substantial cell-to-cell heterogeneity, thus obscuring true phenotypic relationships. Here, we devised a microfluidics system to characterize multiple phenotypes in single yeast cells over time before, during, and after salt stress. The system measured cell and colony size, growth rate, and cell-cycle phase along with nuclear trans-localization of two transcription factors: stress-activated Msn2 that regulates defense genes and Dot6 that represses ribosome biogenesis genes during an active stress response. By tracking cells dynamically, we discovered unexpected discordance between Msn2 and Dot6 behavior that revealed subpopulations of cells with distinct growth properties. Surprisingly, post-stress growth recovery was positively corelated with activation of the Dot6 repressor. In contrast, cells lacking Dot6 displayed slower growth acclimation, even though they grow normally in the absence of stress. We show that wild-type cells with a larger Dot6 response display faster production of Msn2-regulated Ctt1 protein, separable from the contribution of Msn2. These results are consistent with the model that transcriptional repression during acute stress in yeast provides a protective response, likely by redirecting translational capacity to induced transcripts.

Predicting nicotine metabolism across ancestries using genotypes.

BACKGROUND: There is a need to match characteristics of tobacco users with cessation treatments and risks of tobacco attributable diseases such as lung cancer. The rate in which the body metabolizes nicotine has proven an important predictor of these outcomes. Nicotine metabolism is primarily catalyzed by the enzyme cytochrone P450 (CYP2A6) and CYP2A6 activity can be measured as the ratio of two nicotine metabolites: trans-3'-hydroxycotinine to cotinine (NMR). Measurements of these metabolites are only possible in current tobacco users and vary by biofluid source, timing of collection, and protocols; unfortunately, this has limited their use in clinical practice. The NMR depends highly on genetic variation near CYP2A6 on chromosome 19 as well as ancestry, environmental, and other genetic factors. Thus, we aimed to develop prediction models of nicotine metabolism using genotypes and basic individual characteristics (age, gender, height, and weight). RESULTS: We identified four multiethnic studies with nicotine metabolites and DNA samples. We constructed a 263 marker panel from filtering genome-wide association scans of the NMR in each study. We then applied seven machine learning techniques to train models of nicotine metabolism on the largest and most ancestrally diverse dataset (N=2239). The models were then validated using the other three studies (total N=1415). Using cross-validation, we found the correlations between the observed and predicted NMR ranged from 0.69 to 0.97 depending on the model. When predictions were averaged in an ensemble model, the correlation was 0.81. The ensemble model generalizes well in the validation studies across ancestries, despite differences in the measurements of NMR between studies, with correlations of: 0.52 for African ancestry, 0.61 for Asian ancestry, and 0.46 for European ancestry. The most influential predictors of NMR identified in more than two models were rs56113850, rs11878604, and 21 other genetic variants near CYP2A6 as well as age and ancestry. CONCLUSIONS: We have developed an ensemble of seven models for predicting the NMR across ancestries from genotypes and age, gender and BMI. These models were validated using three datasets and associate with nicotine dosages. The knowledge of how an individual metabolizes nicotine could be used to help select the optimal path to reducing or quitting tobacco use, as well as, evaluating risks of tobacco use.

Frailty Risks of Prescription Analgesics and Sedatives across Frailty Models: the Health and Retirement Study.

INTRODUCTION: Limited evidence for incident frailty risks associated with prescription analgesics and sedatives in older (≥ 65 years) community-living adults prompted a more comprehensive investigation. METHODS: We used data from older Health and Retirement Study respondents and three frailty models (frailty index, functional domain, frailty phenotype with 8803, 10,470, and 6850 non-frail individuals, respectively) and estimated sub-hazard ratios of regular prescription drug use (co-use, analgesic use, and sedative use), by frailty model. We addressed confounding with covariate adjustment and propensity score matching approaches. RESULTS: The baseline prevalence of analgesic and sedative co-use, analgesic use, and sedative use among non-frail respondents was 1.8%, 12.8%, and 4.7% for the frailty index model, 4.2%, 16.2%, and 5.3% for the functional domain model, and 4.3%, 15.4%, and 6.1% for the frailty phenotype model, respectively. Cumulative frailty incidence over 10 years was 39.3%, 36.1%, and 14.2% for frailty index, functional domain, and frailty phenotype models, respectively; covariate-adjusted sub-hazard ratio estimates were 2.00 (1.63-2.45), 1.83 (1.57-2.13), and 1.68 (1.21-2.33) for co-use; 1.72 (1.56-1.89), 1.38 (1.27-1.51), and 1.51 (1.27-1.79) for analgesic use; and 1.46 (1.24-1.72), 1.25 (1.07-1.46), and 1.31 (0.97-1.76) for sedative use. Frailty risk ranking (co-use > analgesic use > sedative use) persisted across all model sensitivity analyses. DISCUSSION: Consistently significant frailty risk estimates of regular prescription analgesic and sedative co-use and of prescription analgesic use support existing clinical, public health, and regulatory guidance on opioid and benzodiazepine co-prescription, on opioid prescription, and on NSAID prescription. Frailty phenotype measurement administration limited power to detect significant frailty risks. Research into specific pharmaceutical exposures and comparison of results across cohorts will be required to contribute to the deprescribing evidence base.

Assessing Opioid Use Disorder Treatments in Trials Subject to Non-Adherence via a Functional Generalized Linear Mixed-Effects Model.

The opioid crisis in the United States poses a major threat to public health due to psychiatric and infectious disease comorbidities and death due to opioid use disorder (OUD). OUD is characterized by patterns of opioid misuse leading to persistent heavy use and overdose. The standard of care for treatment of OUD is medication-assisted treatment, in combination with behavioral therapy. Medications for opioid use disorder have been shown to improve OUD outcomes, including reduction and prevention of overdose. However, understanding the effectiveness of such medications has been limited due to non-adherence to assigned dose levels by study patients. To overcome this challenge, herein we develop a model that views dose history as a time-varying covariate. Proceeding in this fashion allows the model to estimate dose effect while accounting for lapses in adherence. The proposed model is used to conduct a secondary analysis of data collected from six efficacy and safety trials of buprenorphine maintenance treatment. This analysis provides further insight into the time-dependent treatment effects of buprenorphine and how different dose adherence patterns relate to risk of opioid use.

Effects of Buprenorphine Dose and Therapeutic Engagement on Illicit Opiate Use in Opioid Use Disorder Treatment Trials.

The impact of agonist dose and of physician, staff and patient engagement on treatment have not been evaluated together in an analysis of treatment for opioid use disorder. Our hypotheses were that greater agonist dose and therapeutic engagement would be associated with reduced illicit opiate use in a time-dependent manner. Publicly-available treatment data from six buprenorphine efficacy and safety trials from the Federally-supported Clinical Trials Network were used to derive treatment variables. Three novel predictors were constructed to capture the time weighted effects of buprenorphine dosage (mg buprenorphine per day), dosing protocol (whether physician could adjust dose), and clinic visits (whether patient attended clinic). We used time-in-trial as a predictor to account for the therapeutic benefits of treatment persistence. The outcome was illicit opiate use defined by self-report or urinalysis. Trial participants (N = 3022 patients with opioid dependence, mean age 36 years, 33% female, 14% Black, 16% Hispanic) were analyzed using a generalized linear mixed model. Treatment variables dose, Odds Ratio (OR) = 0.63 (95% Confidence Interval (95%CI) 0.59−0.67), dosing protocol, OR = 0.70 (95%CI 0.65−0.76), time-in-trial, OR = 0.75 (95%CI 0.71−0.80) and clinic visits, OR = 0.81 (95%CI 0.76−0.87) were significant (p-values < 0.001) protective factors. Treatment implications support higher doses of buprenorphine and greater engagement of patients with providers and clinic staff.

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Pharmacotherapy for smoking cessation: effects by subgroup defined by genetically informed biomarkers.

This review has been withdrawn because it has been found to be in breach of the Cochrane Commercial Sponsorship policy clause 2:  'Individuals who are currently employed or where employed any time in the last three years by a company that has a real or potential financial interest in the outcome of the review (including but not limited to drug companies or medical device manufacturers); or who hold or have applied for a patent related to the review are prohibited from being Cochrane Review authors. In most cases, current or previous employment would be characterized by the affiliation statement made by the author at the title registration, protocol, or review stage of the review'.

Thromboprophylaxis for Children Post-Fontan Procedure: Insights From the UNIVERSE Study.

Background Patients with single-ventricle physiology who undergo the Fontan procedure are at risk for thrombotic events associated with significant morbidity and mortality. The UNIVERSE Study evaluated the efficacy and safety of a novel liquid rivaroxaban formulation, using a body weight-adjusted dosing regimen, versus acetylsalicylic acid (ASA) in children post-Fontan. Methods and Results The UNIVERSE Study was a randomized, multicenter, 2-part, open-label study of rivaroxaban, in children who had undergone a Fontan procedure, to evaluate its dosing regimen, safety, and efficacy. Part A was the single-arm part of the study that determined the pharmacokinetics/pharmacodynamics and safety of rivaroxaban in 12 participants before proceeding to part B, whereby 100 participants were randomized 2:1 to open-label rivaroxaban versus ASA. The study period was 12 months. A total of 112 participants were enrolled across 35 sites in 10 countries. In part B, for safety outcomes, major bleeding occurred in one participant on rivaroxaban (epistaxis that required transfusion). Clinically relevant nonmajor bleeding occurred in 6% of participants on rivaroxaban versus 9% on ASA. Trivial bleeding occurred in 33% of participants on rivaroxaban versus 35% on ASA. For efficacy outcomes, 1 participant on rivaroxaban in part B had a pulmonary embolism (2% overall event rate); and for ASA, 1 participant had ischemic stroke and 2 had venous thrombosis (9% overall event rate). Conclusions In this study, participants who received rivaroxaban for thromboprophylaxis had a similar safety profile and fewer thrombotic events, albeit not statistically significant, compared with those in the ASA group. Registration URL: https://www.clinicaltrials.gov. Identifier: NCT02846532.

Multiethnic Prediction of Nicotine Biomarkers and Association With Nicotine Dependence.

INTRODUCTION: The nicotine metabolite ratio and nicotine equivalents are measures of metabolism rate and intake. Genome-wide prediction of these nicotine biomarkers in multiethnic samples will enable tobacco-related biomarker, behavioral, and exposure research in studies without measured biomarkers. AIMS AND METHODS: We screened genetic variants genome-wide using marginal scans and applied statistical learning algorithms on top-ranked genetic variants, age, ethnicity and sex, and, in additional modeling, cigarettes per day (CPD), (in additional modeling) to build prediction models for the urinary nicotine metabolite ratio (uNMR) and creatinine-standardized total nicotine equivalents (TNE) in 2239 current cigarette smokers in five ethnic groups. We predicted these nicotine biomarkers using model ensembles and evaluated external validity using dependence measures in 1864 treatment-seeking smokers in two ethnic groups. RESULTS: The genomic regions with the most selected and included variants for measured biomarkers were chr19q13.2 (uNMR, without and with CPD) and chr15q25.1 and chr10q25.3 (TNE, without and with CPD). We observed ensemble correlations between measured and predicted biomarker values for the uNMR and TNE without (with CPD) of 0.67 (0.68) and 0.65 (0.72) in the training sample. We observed inconsistency in penalized regression models of TNE (with CPD) with fewer variants at chr15q25.1 selected and included. In treatment-seeking smokers, predicted uNMR (without CPD) was significantly associated with CPD and predicted TNE (without CPD) with CPD, time-to-first-cigarette, and Fagerström total score. CONCLUSIONS: Nicotine metabolites, genome-wide data, and statistical learning approaches developed novel robust predictive models for urinary nicotine biomarkers in multiple ethnic groups. Predicted biomarker associations helped define genetically influenced components of nicotine dependence. IMPLICATIONS: We demonstrate development of robust models and multiethnic prediction of the uNMR and TNE using statistical and machine learning approaches. Variants included in trained models for nicotine biomarkers include top-ranked variants in multiethnic genome-wide studies of smoking behavior, nicotine metabolites, and related disease. Association of the two predicted nicotine biomarkers with Fagerström Test for Nicotine Dependence items supports models of nicotine biomarkers as predictors of physical dependence and nicotine exposure. Predicted nicotine biomarkers may facilitate tobacco-related disease and treatment research in samples with genomic data and limited nicotine metabolite or tobacco exposure data.

Developmental outcomes after early surgery for complex congenital heart disease: a systematic review and meta-analysis.

AIM: (1) To systematically review the literature on developmental outcomes from infancy to adolescence of children with complex congenital heart disease (CHD) who underwent early surgery; (2) to run a meta-regression analysis on the Bayley Scales of Infant Development, Second Edition Mental Developmental Index and Psychomotor Developmental Index (PDI) of infants up to 24 months and IQs of preschool-aged children to adolescents; (3) to assess associations between perioperative risk factors and outcomes. METHOD: We searched pertinent literature (January 1990 to January 2019) in PubMed, Embase, CINAHL, and PsycINFO. Selection criteria included infants with complex CHD who had primary surgery within the first 9 weeks of life. Methodological quality, including risk of bias and internal validity, were assessed. RESULTS: In total, 185 papers met the inclusion criteria; the 100 with high to moderate methodological quality were analysed in detail. Substantial heterogeneity in the group with CHD and in methodology existed. The outcome of infants with single-ventricle CHD was inferior to those with two-ventricle CHD (respectively: average scores for PDI 77 and 88; intelligence scores 92 and 98). Perioperative risk factors were inconsistently associated with developmental outcomes. INTERPRETATION: The literature on children undergoing surgery in early infancy suggests that infants with a single ventricle are at highest risk of adverse developmental outcomes.