Sleep, Classroom Behavior, and Achievement Among Children of Color in Historically Disinvested Neighborhoods.

Children of color are more likely to have poor sleep health than White children, placing them at risk for behavioral problems in the classroom and lower academic performance. Few studies, however, have utilized standardized measures of both classroom behavior and achievement. This study examined whether children's sleep (parent and teacher report) in first grade concurrently related to independent observations of classroom behavior and longitudinally predicted achievement test scores in second grade in a sample of primarily Black (86%) children (n = 572; age = 6.8) living in historically disinvested neighborhoods. Higher teacher-reported child sleepiness was associated with lower adaptive behaviors and higher problem behaviors in the classroom, and predicted lower achievement. Parent-reported bedtime resistance and disordered breathing also predicted lower achievement.

Can a Parenting Intervention to Prevent Early Conduct Problems Interrupt Girls' Risk for Intimate Partner Violence 10 Years Later?

This study tests whether a parenting intervention for families of preschoolers at risk for conduct problems can prevent later risk for intimate partner violence (IPV). Ninety-nine preschoolers at familial risk for conduct problems were randomly assigned to intervention or control conditions. Ten years later, 45 preschoolers and 43 of their siblings completed an assessment of their romantic relationships, including measures of physical and psychological IPV. The study focuses on the 54 females, including targets (n = 27) and siblings (n = 27) who participated in a 10-year follow-up (M age = 16.5, SD = 5.2, range = 10-28). Using an intent-to-treat (ITT) design, multivariate regressions suggest that females from families randomly assigned to intervention in early childhood scored lower than those in the control condition on perceptions of dating violence as normative, beliefs about IPV prevalence, exposure to IPV in their own peer group, and expected sanction behaviors for IPV perpetration and victimization. Findings suggest that early parenting intervention may reduce association of high-risk females with aggressive peers and partners in adolescence.

Potential return on investment of a family-centered early childhood intervention: a cost-effectiveness analysis.

BACKGROUND: ParentCorps is a family-centered enhancement to pre-kindergarten programming in elementary schools and early education centers. When implemented in high-poverty, urban elementary schools serving primarily Black and Latino children, it has been found to yield benefits in childhood across domains of academic achievement, behavior problems, and obesity. However, its long-term cost-effectiveness is unknown. METHODS: We determined the cost-effectiveness of ParentCorps in high-poverty, urban schools using a Markov Model projecting the long-term impact of ParentCorps compared to standard pre-kindergarten programming. We measured costs and quality adjusted life years (QALYs) resulting from the development of three disease states (i.e., drug abuse, obesity, and diabetes); from the health sequelae of these disease states; from graduation from high school; from interaction with the judiciary system; and opportunity costs of unemployment with a lifetime time horizon. The model was built, and analyses were performed in 2015-2016. RESULTS: ParentCorps was estimated to save $4387 per individual and increase each individual's quality adjusted life expectancy by 0.27 QALYs. These benefits were primarily due to the impact of ParentCorps on childhood obesity and the subsequent predicted prevention of diabetes, and ParentCorps' impact on childhood behavior problems and the subsequent predicted prevention of interaction with the judiciary system and unemployment. Results were robust on sensitivity analyses, with ParentCorps remaining cost saving and health generating under nearly all assumptions, except when schools had very small pre-kindergarten programs. CONCLUSIONS: Effective family-centered interventions early in life such as ParentCorps that impact academic, behavioral and health outcomes among children attending high-poverty, urban schools have the potential to result in longer-term health benefits and substantial cost savings.

Change in depression across adolescence: The role of early anger socialization and child anger.

The purpose of this longitudinal study was to examine the relations of early socialization of anger with change in adolescent depression, and moderation by child anger. Using a sample of low-income, ethnic minority children at familial risk for psychopathology in the United States (n = 92; ages 3-5; 53% female; 65% African American; 27% Latina/o), early anger socialization (i.e., parent response to child anger) was tested as a predictor of change in depression from preadolescence to adolescence [i.e., age 8 (n = 63), 11 (n = 58), and 13 (n = 44)]. A videotaped parent-child interaction was coded for parental socialization of preschooler anger, and psychiatric interviews of depression were conducted three times across preadolescence and adolescence. Major depression diagnoses increased from preadolescence to adolescence. Latent growth modeling indicated parent discouragement of child anger was a significant predictor of an increase in the child's later depression from preadolescence to adolescence, and child anger intensity was a significant moderator.

A population-level approach to promoting healthy child development and school success in low-income, urban neighborhoods: impact on parenting and child conduct problems.

Minority children living in disadvantaged neighborhoods are at high risk for school dropout, delinquency, and poor health, largely due to the negative impact of poverty and stress on parenting and child development. This study evaluated a population-level, family-centered, school-based intervention designed to promote learning, behavior, and health by strengthening parenting, classroom quality, and child self-regulation during early childhood. Ten schools in urban districts serving primarily low-income Black students were randomly assigned to intervention or a "pre-kindergarten education as usual" control condition. Intervention included a family program (a 13-week behavioral parenting intervention and concurrent group for children) and professional development for early childhood teachers. The majority (88 %) of the pre-kindergarten population (N = 1,050; age 4) enrolled in the trial, and nearly 60 % of parents in intervention schools participated in the family program. This study evaluated intervention impact on parenting (knowledge, positive behavior support, behavior management, involvement in early learning) and child conduct problems over a 2-year period (end of kindergarten). Intent-to-treat analyses found intervention effects on parenting knowledge, positive behavior support, and teacher-rated parent involvement. For the highest-risk families, intervention also resulted in increased parent-rated involvement in early learning and decreased harsh and inconsistent behavior management. Among boys at high risk for problems based on baseline behavioral dysregulation (age 4, 23 % of sample), intervention led to lower rates of conduct problems at age 6. Family-centered intervention at the transition to school has potential to improve population health and break the cycle of disadvantage for low-income, minority families.

Early Academic Achievement Among American Low-Income Black Students from Immigrant and Non-Immigrant Families.

At least half of the well-documented achievement gap for low-income Black children is already present in kindergarten, due in part to limited opportunities for acquiring foundational skills necessary for school success. There is some evidence that low-income minority children from immigrant families have more positive outcomes than their non-immigrant counterparts, although little is known about how the immigrant paradox may manifest in young children. This study examines foundational school readiness skills (academic and social-emotional learning) at entry into pre-kindergarten (pre-k) and achievement in kindergarten and second grade among Black children from low-income immigrant and non-immigrant families (N = 299). Immigrant and non-immigrant children entered pre-k with comparable readiness scores; in both groups, reading scores decreased significantly from kindergarten to second grade and math scores decreased significantly for non-immigrant children and marginally for immigrant children. Regardless of immigrant status, pre-k school readiness and pre-k classroom quality were associated with elementary school achievement. However, declines in achievement scores were not as steep for immigrant children and several predictive associations were moderated by immigrant status, such that among those with lower pre-k school readiness or in lower quality classrooms, immigrant children had higher achievement test scores than children from non-immigrant families. Findings suggest that immigrant status provides young Black students with some protection against individual- and classroom-level risk factors for early underachievement in elementary school.

Reasons for recent marijuana use in relation to use of other illicit drugs among high school seniors in the United States.

OBJECTIVES: Studies show that illicit cannabis (marijuana) use is related to use of other illicit drugs and that reasons for use are related to frequency of marijuana use. However, research is needed to examine whether specific reasons for marijuana use are associated with use of other illicit drugs. METHODS: Data from recent marijuana-using high school seniors were examined from 12 cohorts of Monitoring the Future (Weighted n = 6481) to examine whether reasons for recent marijuana use are associated with use of eight other illicit drugs. RESULTS: Using "to experiment" decreased odds of reporting use of each drug and using to decrease effects of other drugs increased odds of reporting use of each drug. In multivariable models, using marijuana "to experiment" decreased the odds for reporting use of hallucinogens other than LSD and narcotics other than heroin. Using marijuana for "insight" increased the odds for use of hallucinogens other than LSD, and use due to "boredom" increased the odds for reporting use of powder cocaine and hallucinogens other than LSD. Using marijuana to increase effects of other drugs increased odds of reporting use of each of the eight drugs, and using it to decrease other drug effects increased odds of reporting use of crack, hallucinogens other than LSD, and amphetamine/stimulants. CONCLUSIONS: This study helped identify illicit marijuana users who are more likely to report use of other illicit drugs. Prevention efforts need to focus on students who report certain reasons for marijuana use as they may be at risk for use of other illicit drugs.

Family and Teacher Characteristics as Predictors of Parent Involvement in Education During Early Childhood Among Afro-Caribbean and Latino Immigrant Families.

Parent involvement is a robust predictor of academic achievement, but little is known about school- and home-based involvement in immigrant families. Drawing on ecological theories, the present study examined contextual characteristics as predictors of parent involvement among Afro-Caribbean and Latino parents of young students in urban public schools. Socioeconomic disadvantage was associated with lower home-based involvement. Several factors were associated with higher involvement, including parents' connection to their culture of origin and to U.S. culture, engagement practices by teachers and parent-teacher ethnic consonance (for Latinos only). Findings have implications for promoting involvement among immigrant families of students in urban schools.

Moderators of intervention effects on parenting practices in a randomized controlled trial in early childhood.

The current study examined whether parent psychological resources (parenting stress, depression, and social support from friends and family) moderated the effects of early family preventive intervention on parenting among high-risk families. Ninety-two preschool-age children (M age = 3.94 years) at familial risk for conduct problems participated in a randomized controlled trial of a family intervention to prevent conduct problems. The majority of families were African American or Latino and experienced multiple stressors associated with poverty and familial antisocial behavior. Families were randomized to a 22-session group-based intervention or to a no-intervention, assessment-only control condition. Parents reported on their psychological resources (parenting stress, depression and social support from friends and family) at baseline. Parenting (responsive, harsh, stimulation for learning) was assessed through self-report and observational measures four times over 24 months. Previously-reported intervention effects on responsive parenting and stimulation for learning were moderated by depression and social support from friends, respectively, such that benefits were concentrated among those at greatest risk (i.e., depressed, limited support from friends). The intervention effect on harsh parenting was not moderated by any of the parent psychological resources examined, such that parents with high and low resources benefited comparably. Consideration of moderators of preventive intervention effects on parenting provides important information about intervention impact among families experiencing multiple barriers to engagement and effective parenting. Findings suggest that parents with diminished psychological resources are just as likely to benefit. Family-focused, group-based intervention is promising for strengthening parenting among the highest risk families.

An examination of sociodemographic correlates of ecstasy use among high school seniors in the United States.

BACKGROUND: Although ecstasy (MDMA) use is not as prevalent in the United States (US) as it was in the early 2000s, use remains popular among adolescents and young adults. Few recent studies have examined ecstasy use in national samples among those at particularly high risk for use-adolescents approaching adulthood. Research is needed to delineate sociodemographic correlates of use in this group. METHODS: Data were examined from a nationally representative sample of high school seniors in the US (modal age = 18) from the Monitoring the Future study (years 2007-2012; weighted N = 26,504). Data from all cohorts were aggregated and correlates of recent (last 12-month) use of ecstasy were examined. RESULTS: Roughly 4.4% of high school seniors reported use of ecstasy within the last year. Females and religious students were consistently at lower odds for use. Black and Hispanic students, and students residing with two parents, were at lower odds for ecstasy use, until controlling for other drug use. Odds of use were consistently increased for those residing in a city, students with weekly income of >$50 from a job, and students earning >$10 weekly from other sources. Lifetime use of alcohol, cigarettes, marijuana, and other illicit drugs each robustly increased odds of ecstasy use. CONCLUSION: Subgroups of high school seniors, defined by specific sociodemographic factors, and those who have used other drugs, are currently at high risk for ecstasy initiation and use. Since ecstasy is regaining popularity in the US, prevention efforts should consider these factors.

Out Like a Light: Feasibility and Acceptability Study of an Audio-Based Sleep Aide for Improving Parent-Child Sleep Health.

Our study examines the acceptability and feasibility of Moshi, an audio-based mobile application, among children 3-8 years old using a parent-child dyadic approach. Our 10-day within-subject pre-post study design consisted of five nights of a normal bedtime routine and a subsequent five nights exposed to one story on the Moshi application during the intervention. Each five-night period spanned three weeknights and two weekend nights. The Short-Form Children's Sleep Habits Questionnaire (SF-CSHQ) was used to measure children's sleep at baseline and post-intervention. The PROMIS, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index were used to assess parents' sleep. Among the 25 child-parent dyads, the mean child age was 4 (SD = 1.23) and 63% were male (n = 15). Mean parent age was 35 (SD = 5.83), 84% were female (n = 21), and 48.0% were Black (n = 12). For child-only comparisons, mean post-SF-CSHQ measures were lower compared to baseline. A trend in parent sleep is reported. This study shows the potential of an audio-based mobile sleep aid to improve sleep health in a racially diverse parent and child dyad sample.

A quasi-experimental study of parent and child well-being in families of color in the context of COVID-19 related school closure.

Families of color living in historically disinvested neighborhoods face a multitude of health disparities which have been exacerbated by COVID-19 and the resulting strategies to mitigate its transmission. School closure, which occurred with little warning and few, if any, resources for preparation, disrupted multiple aspects of families' lives; these disruptions are anticipated to adversely impact mental health and well-being. The current study aims to advance understanding of the experiences of families of young children of color during the pandemic by utilizing a natural experiment design to test impact on child and parent mental health and sleep in the context of COVID-19 related school closure among families in historically disinvested neighborhoods. Data from this study come from an ongoing study of 281 families of color enrolled in 41 pre-kindergarten (pre-K) programs in neighborhoods across New York City (NYC). In NYC, school closure occurred on March 16, 2020, during a data collection period involving phone surveys with parents; the quasi-experimental design allows for comparison of the 198 families who had completed the survey prior to March 16, and the 83 families who completed the survey after March 16, using identical protocols and procedures. Results demonstrate poorer mental health among parents surveyed after school closure as compared to before school closure. No differences were found for parent sleep, child mental health, or child sleep. Implications of this work highlight the need for structural and systemic supports for families faced with compounding stressors as a result of the COVID-19 pandemic and related school closure.

Parental perceived immigration threat and children's mental health, self-regulation and executive functioning in pre-Kindergarten.

Many children in immigrant households endure unique stressors shaped by national, state, and local immigration policies and enforcement activity in the United States. Qualitative studies find that during times of heightened immigration enforcement, children as young as 3 years of age show signs of behavioral distress related to national anti-immigrant sentiment and the possibility of losing a parent. Using multiple sources of data from 168 racially and ethnically diverse families of children in pre-Kindergarten, the present study examined variability in perceived levels of immigration enforcement threat by parental immigrant status and ethnicity. This study examined associations between immigration enforcement threat and child mental health, self-regulation, and executive functioning and whether parent immigrant status or child gender moderates these associations. We found substantial variability in perceived immigration threat, with immigrant parents and Latinx parents reporting significantly greater levels of immigration threat compared to nonimmigrant parents and non-Latinx parents. Immigration enforcement threat was associated with greater child separation anxiety and overanxious behaviors, and lower self-regulation among boys and girls and among children of immigrant and U.S.-born parents. In contrast to our hypothesis, immigration enforcement threat was associated with higher self-regulation according to independent assessor ratings. Educators and healthcare providers working with young children from immigrant and Latinx households should be aware of the disproportionate stress experienced by immigrant and Latinx families due to a xenophobic sociopolitical climate marked by heightened immigration enforcement threat and racist, anti-immigrant rhetoric. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Measuring Children's Emotion Knowledge: Steps Toward an Anti-Racist Approach to Early Childhood Assessments.

Emotion knowledge (EK) is a malleable set of skills that is central to social interactions and school success during early childhood. The current study describes an anti-racist approach to adapting an EK measure that assesses knowledge of facial expressions to be ecologically valid for young children of color attending pre-Kindergarten (pre-K) programs in a large urban school district. This approach involved (1) attending to race/ethnicity in selection of visual stimuli, (2) ensuring appropriate translation and language for administration, and (3) exploring the functioning of the measure within a racially, ethnically, and linguistically diverse group of children. A total of 235 children (67.4% Latinx, 14.1% non-Latinx Black, 7.1% non-Latinx White, 7.8% Asian, 3.6% another racial/ethnicity) were assessed in English (74%) or Spanish (26%) during the fall of pre-K (mean age = 4.4). Both English and Spanish versions appear to have similar reliability, although accuracy levels were lower when administered in Spanish. No differences in mean accuracy scores were found across racial/ethnic groups or for boys versus girls. This study contributes to the growing literature necessary to advance anti-racist research in affective science. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-022-00105-w.

Promoting effective parenting practices and preventing child behavior problems in school among ethnically diverse families from underserved, urban communities.

This study examines the efficacy of ParentCorps among 4-year-old children (N = 171) enrolled in prekindergarten in schools in a large urban school district. ParentCorps includes a series of 13 group sessions for parents and children held at the school during early evening hours and facilitated by teachers and mental health professionals. ParentCorps resulted in significant benefits on effective parenting practices and teacher ratings of child behavior problems in school. Intervention effects were of similar magnitude for families at different levels of risk and for Black and Latino families. The number of sessions attended was related to improvements in parenting. Study findings support investment in and further study of school-based family interventions for children from underserved, urban communities.

Understanding relations among early family environment, cortisol response, and child aggression via a prevention experiment.

This study examined relations among family environment, cortisol response, and behavior in the context of a randomized controlled trial with 92 children (M = 48 months) at risk for antisocial behavior. Previously, researchers reported an intervention effect on cortisol response in anticipation of a social challenge. The current study examined whether changes in cortisol response were related to later child aggression. Among lower warmth families, the intervention effect on aggression was largely mediated by the intervention effect on cortisol response. Although the intervention also resulted in significant benefits on child engaging behavior, cortisol response did not mediate this effect. These findings demonstrate meaningful associations between cortisol response and aggression among children at familial risk for antisocial behavior.

The Role of Emotion Understanding in the Development of Aggression and Callous-Unemotional Features across Early Childhood.

Although prior research suggests that children show rapid change in socioemotional functioning and aggression throughout early childhood, little is known about how these factors may be associated with the development of callous-unemotional (CU) features. This study investigated the parallel development of, and reciprocal relationships between, emotion understanding (EU) and aggression across early childhood, as well as how they play a role in the development of CU features. Parallel latent growth curve modeling was used to examine longitudinal reciprocal relationships between EU and aggression in a sample of 498 primarily Black (i.e., African-American or Afro-Caribbean) preschoolers (49.5% male, 89.2% Black, Mage = 4.1), followed with six waves over a 45-month period from pre-kindergarten through grade 2. CU features were included as a baseline covariate, as well as an outcome, of EU and aggression growth factors. Children with lower levels of EU at age 4 displayed higher linear increases in aggression over time. EU at age 4 had a significant indirect effect on CU features at age 8 via its association with linear increases in aggression. Findings suggest that EU is influential in the early development of aggression, which may in turn influence the development or exacerbation of CU features. Children's EU in early childhood, especially concerning others' distress, may be an important component of preventive intervention efforts for young children at risk for serious antisocial behavior.

Effects of a psychosocial family-based preventive intervention on cortisol response to a social challenge in preschoolers at high risk for antisocial behavior.

CONTEXT: Salivary cortisol levels during social challenge relate to adaptive functioning in children and adults. Low cortisol levels have been related to conduct problems and antisocial behavior. Although studies in rodents implicate early-life social experience in cortisol regulation, no studies with humans have examined the effects of an experimentally manipulated early-life social experience on cortisol regulation. OBJECTIVE: To examine the effects of experimental manipulations of social experience on cortisol response to a social challenge in preschoolers at risk for antisocial behavior. DESIGN: Randomized controlled trial. SETTING: Department of Child and Adolescent Psychiatry, New York University School of Medicine. PARTICIPANTS: Ninety-two preschool-age siblings of youths adjudicated for delinquent acts. Intervention Family-based intervention included 22 weekly group sessions for parents and preschoolers and 10 biweekly home visits conducted during a 6- to 8-month period. MAIN OUTCOME MEASURES: Salivary cortisol levels before and after a social challenge (entry into an unfamiliar peer group). RESULTS: Relative to controls, children in the intervention condition had increased cortisol levels in anticipation of the peer social challenge. Increases were relative to both preintervention cortisol levels during the challenge and cortisol levels in the home, which were not altered by the intervention. CONCLUSIONS: A family-based preventive intervention for children at high risk for antisocial behavior alters stress response in anticipation of a peer social challenge. The experimentally induced change in cortisol levels parallels patterns found in normally developing, low-risk children.

Unpacking Partnership, Engagement, and Collaboration Research to Inform Implementation Strategies Development: Theoretical Frameworks and Emerging Methodologies.

Background: Partnership, engagement, and collaboration (PEC) are critical factors in dissemination and implementation (D&I) research. Despite a growing recognition that incorporating PEC strategies in D&I research is likely to increase the relevance, feasibility, impacts, and of evidence-based interventions or practices (EBIs, EBPs), conceptual frameworks and methodologies to guide the development and testing of PEC strategies in D&I research are lacking. To address this methodological gap, a review was conducted to summarize what we know, what we think we know, and what we need to know about PEC to inform D&I research. Methods: A cross-field scoping review, drawing upon a broad range of PEC related literature in health, was conducted. Publications reviewed focused on factors influencing PEC, and processes, mechanisms and strategies for promoting effective PEC. The review was conducted separately for three forms of partnerships that are commonly used in D&I research: (1) consumer-provider or patient-implementer partnership; (2) delivery system or implementation team partnership; and (3) sustainment/support or interagency/community partnership. A total of 39 studies, of which 21 were review articles, were selected for an in-depth review. Results: Across three forms of partnerships, four domains (cognitive, interpersonal/affective, behavioral, and contextual domains) were consistently identified as factors and strategies for promoting PEC. Depending on the stage (preparation or execution) and purpose of the partnership (regulating performance or managing maintenance), certain PEC strategies are more or less relevant. Recent developments of PEC frameworks, such as Partnership Stage of Change and multiple dynamic processes, provide more comprehensive conceptual explanations for PEC mechanisms, which can better guide PEC strategies selection and integration in D&I research. Conclusions: This review contributes to D&I knowledge by identifying critical domain factors, processes, or mechanisms, and key strategies for PEC, and offers a multi-level PEC framework for future research to build the evidence base. However, more research is needed to test PEC mechanisms.

Effects of ParentCorps in Prekindergarten on Child Mental Health and Academic Performance: Follow-up of a Randomized Clinical Trial Through 8 Years of Age.

Importance: Low-income minority children living in urban neighborhoods are at high risk for mental health problems and underachievement. ParentCorps, a family-centered, school-based intervention in prekindergarten, improves parenting and school readiness (ie, self-regulation and preacademic skills) in 2 randomized clinical trials. The longer-term effect on child mental health and academic performance is not known. Objective: To examine whether ParentCorps delivered as an enhancement to prekindergarten programs in high-poverty urban schools leads to fewer mental health problems and increased academic performance in the early elementary school years. Design, Setting, and Participants: This is a 3-year follow-up study of a cluster randomized clinical trial of ParentCorps in public schools with prekindergarten programs in New York City. Ten elementary schools serving a primarily low-income, black student population were randomized in 2005, and 4 consecutive cohorts of prekindergarten students were enrolled from September 12, 2005, through December 31, 2008. We report follow-up for the 3 cohorts enrolled after the initial year of implementation. Data analysis was performed from September 1, 2014, to December 31, 2015. Interventions: ParentCorps included professional development for prekindergarten and kindergarten teachers and a program for parents and prekindergarten students (13 two-hour group sessions delivered after school by teachers and mental health professionals). Main Outcomes and Measures: Annual teacher ratings of mental health problems and academic performance and standardized tests of academic achievement in kindergarten and second grade by testers masked to the intervention or control group randomization. Results: A total of 1050 children (4 years old; 518 boys [49.3%] and 532 girls [50.7%]) in 99 prekindergarten classrooms participated in the trial (88.1% of the prekindergarten population), with 792 students enrolled from 2006 to 2008. Most families in the follow-up study (421 [69.6%]) were low income; 680 (85.9%) identified as non-Latino black, 78 (9.8%) as Latino, and 34 (4.3%) as other. Relative to their peers in prekindergarten programs, children in ParentCorps-enhanced prekindergarten programs had lower levels of mental health problems (Cohen d = 0.44; 95% CI, 0.08-0.81) and higher teacher-rated academic performance (Cohen d = 0.21; 95% CI, 0.02-0.39) in second grade. Conclusions and Relevance: Intervention in prekindergarten led to better mental health and academic performance 3 years later. Family-centered early intervention has the potential to prevent problems and reduce disparities for low-income minority children. Trial Registration: clinicaltrials.gov Identifier: NCT01670227.