Passively sensing smartphone use in teens with rates of use by sex and across operating systems.

Youth screen media activity is a growing concern, though few studies include objective usage data. Through the longitudinal, U.S.-based Adolescent Brain Cognitive Development (ABCD) Study, youth (mage = 14; n = 1415) self-reported their typical smartphone use and passively recorded three weeks of smartphone use via the ABCD-specific Effortless Assessment Research System (EARS) application. Here we describe and validate passively-sensed smartphone keyboard and app use measures, provide code to harmonize measures across operating systems, and describe trends in adolescent smartphone use. Keyboard and app-use measures were reliable and positively correlated with one another (r = 0.33) and with self-reported use (rs = 0.21-0.35). Participants recorded a mean of 5 h of daily smartphone use, which is two more hours than they self-reported. Further, females logged more smartphone use than males. Smartphone use was recorded at all hours, peaking on average from 8 to 10 PM and lowest from 3 to 5 AM. Social media and texting apps comprised nearly half of all use. Data are openly available to approved investigators ( https://nda.nih.gov/abcd/ ). Information herein can inform use of the ABCD dataset to longitudinally study health and neurodevelopmental correlates of adolescent smartphone use.

Communications, engagement, and dissemination strategies for the HEALthy Brain and Child Development (HBCD) Study.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Study success depends on the engagement and inclusion of diverse populations of pregnant participants and their children across the United States, including those at high and low risk for prenatal substance use. The Communications, Engagement, and Dissemination (CED) Committee is responsible for the development and implementation of a strategy to promote awareness about the study, encourage participation, and engage HBCD families, community partners, and collaborators. Initial work involved developing versatile recruitment and awareness materials with a consistent and inclusive message that reduces stigma and negative bias towards marginalized populations, including people with substance use and other mental health conditions. These efforts were shaped by an integrated product development workflow and early engagement with HBCD partners to address challenges. Ongoing work includes the expansion of HBCD outreach through newsletters and social media platforms with an emphasis on protecting participant privacy. Future activities will focus on disseminating scientific information through generation of infographics and webinars that will inform participants, families, and the public of discoveries generated from HBCD Study data.

Connectome-based Brain Marker Moderates the Relationship between Childhood Adversity and Transdiagnostic Psychopathology during Early Adolescence.

Importance: Identifying brain-based markers of resiliency that reliably predict who is and is not at elevated risk for developing psychopathology among children who experience adverse childhood experiences (ACEs) is important for improving our mechanistic understanding of these etiological links between child adversity and psychopathology and guiding precision medicine and prevention efforts for reducing psychiatric impact of ACEs. Objective: To examine associations between ACEs and transdiagnostic psychopathology during the transition from preadolescence to early adolescence and test whether these associations are moderated by a hypothesized resilience factor, a previously identified connectome variate (CV) that is associated with higher cognitive function and lower psychopathology. Design Setting and Participants: This study was conducted in a longitudinal design based on multicenter data from a community cohort of U.S. youth aged of 9-11 at baseline, who participated in the Adolescent Brain Cognitive Development (ABCD) study (N=7,382 at baseline and 6,813 at 2-year follow-up). Linear regression models and moderation analyses were used to characterize concurrent and prospective associations between lifetime ACEs and number of DSM-5 psychiatric disorders (indexing transdiagnostic psychopathology) and to determine if individual variations in these associations were moderated by the CV derived from resting-state fMRI at baseline. Main Outcomes and Measures: Cumulative number of current DSM-5 psychiatric disorders assessed using the computerized self-admin version Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5) and lifetime ACEs assessed from child and parent reports at baseline (9-10 years) and 2-year-follow-up (11-12 years). Results: ACE total scores correlated positively with the cumulative number of current DSM-5 psychiatric disorders at both baseline (r =.258, p < .001) and 2-year follow-up (r =.257, p < .001). The baseline CV score moderated the ACE-disorder associations at baseline (B = -0.021, p < .001) and at 2-year follow-up (B = -0.018, p = .008), as well as the association between the changes in ACE and in the number of disorders from baseline to year 2 (B = -0.012, p = .045). Post-hoc analyses further showed that the moderation effect of CV on ACE-psychopathology associations was specific to the threat-related ACEs and to female youth. Conclusions and Relevance: These findings provide preliminary evidence for a connectome-based resiliency marker and suggest that functional connectivity strength in a broad system including frontal-parietal cortices and subcortical nuclei relevant to cognitive control may protect preadolescents who have experienced lifetime ACEs--especially females and those experiencing threat-related ACEs--from developing transdiagnostic psychopathology.

Genome-scale chromatin binding dynamics of RNA Polymerase II general transcription machinery components.

A great deal of work has revealed, in structural detail, the components of the preinitiation complex (PIC) machinery required for initiation of mRNA gene transcription by RNA polymerase II (Pol II). However, less-well understood are the in vivo PIC assembly pathways and their kinetics, an understanding of which is vital for determining how rates of in vivo RNA synthesis are established. We used competition ChIP in budding yeast to obtain genome-scale estimates of the residence times for five general transcription factors (GTFs): TBP, TFIIA, TFIIB, TFIIE and TFIIF. While many GTF-chromatin interactions were short-lived ( < 1 min), there were numerous interactions with residence times in the range of several minutes. Sets of genes with a shared function also shared similar patterns of GTF kinetic behavior. TFIIE, a GTF that enters the PIC late in the assembly process, had residence times correlated with RNA synthesis rates. The datasets and results reported here provide kinetic information for most of the Pol II-driven genes in this organism, offering a rich resource for exploring the mechanistic relationships between PIC assembly, gene regulation, and transcription.

Outcomes After Induction of Labor Compared With Dilation and Evacuation for the Management of Rupture of Membranes in the Second Trimester.

Previable and periviable rupture of membranes is associated with significant morbidity for the pregnant patient. For those who have a choice of options and undergo active management, it is not known how the risks of induction of labor compare with those for dilation and evacuation (D&E). We performed a retrospective cohort study of patients with rupture of membranes between 14 0/7 and 23 6/7 weeks of gestation who opted for active management. Adverse events (52.2% vs 16.9%, P <.01) and time to uterine evacuation greater than 24 hours (26.7% vs 9.6%, P =.01) were more common among patients undergoing induction of labor. In a multivariable regression, induction of labor was an independent risk factor for complications (odds ratio 5.70, 95% CI, 2.35-13.82) compared with D&E. Severe complications were rare across both groups (4.4% for patients undergoing induction vs 2.6% for D&E, P =.63). Given the differing risks by termination method, access to D&E is an important treatment option for this patient population.

Genome-scale chromatin interaction dynamic measurements for key components of the RNA Pol II general transcription machinery.

Background: A great deal of work has revealed in structural detail the components of the machinery responsible for mRNA gene transcription initiation. These include the general transcription factors (GTFs), which assemble at promoters along with RNA Polymerase II (Pol II) to form a preinitiation complex (PIC) aided by the activities of cofactors and site-specific transcription factors (TFs). However, less well understood are the in vivo PIC assembly pathways and their kinetics, an understanding of which is vital for determining on a mechanistic level how rates of in vivo RNA synthesis are established and how cofactors and TFs impact them. Results: We used competition ChIP to obtain genome-scale estimates of the residence times for five GTFs: TBP, TFIIA, TFIIB, TFIIE and TFIIF in budding yeast. While many GTF-chromatin interactions were short-lived (< 1 min), there were numerous interactions with residence times in the several minutes range. Sets of genes with a shared function also shared similar patterns of GTF kinetic behavior. TFIIE, a GTF that enters the PIC late in the assembly process, had residence times correlated with RNA synthesis rates. Conclusions: The datasets and results reported here provide kinetic information for most of the Pol II-driven genes in this organism and therefore offer a rich resource for exploring the mechanistic relationships between PIC assembly, gene regulation, and transcription. The relationships between gene function and GTF dynamics suggest that shared sets of TFs tune PIC assembly kinetics to ensure appropriate levels of expression.

The yeast Dbf4 Zn2+ finger domain suppresses single-stranded DNA at replication forks initiated from a subset of origins.

Dbf4 is the cyclin-like subunit for the Dbf4-dependent protein kinase (DDK), required for activating the replicative helicase at DNA replication origin that fire during S phase. Dbf4 also functions as an adaptor, targeting the DDK to different groups of origins and substrates. Here we report a genome-wide analysis of origin firing in a budding yeast mutant, dbf4-zn, lacking the Zn2+ finger domain within the C-terminus of Dbf4. At one group of origins, which we call dromedaries, we observe an unanticipated DNA replication phenotype: accumulation of single-stranded DNA spanning ± 5kbp from the center of the origins. A similar accumulation of single-stranded DNA at origins occurs more globally in pri1-m4 mutants defective for the catalytic subunit of DNA primase and rad53 mutants defective for the S phase checkpoint following DNA replication stress. We propose the Dbf4 Zn2+ finger suppresses single-stranded gaps at replication forks emanating from dromedary origins. Certain origins may impose an elevated requirement for the DDK to fully initiate DNA synthesis following origin activation. Alternatively, dbf4-zn may be defective for stabilizing/restarting replication forks emanating from dromedary origins during replication stress.

Measurement of gender and sexuality in the Adolescent Brain Cognitive Development (ABCD) study.

The Adolescent Brain Cognitive DevelopmentSM (ABCD) study is a longitudinal study of adolescent brain development and health that includes over 11,800 youth in the United States. The ABCD study includes broad developmental domains, and gender and sexuality are two of these with noted changes across late childhood and early adolescence. The Gender Identity and Sexual Health (GISH) workgroup recommends measures of gender and sexuality for the ABCD study, prioritizing those that are developmentally sensitive, capture individual differences in the experience of gender and sexuality, and minimize participant burden. This manuscript describes the gender and sexuality measures used in ABCD and provides guidance for researchers using these data. Data showing the utility of these measures and longitudinal trends are presented. Including assessment of gender and sexuality in ABCD allows for characterization of developmental trajectories of gender and sexuality, and the broad scope of ABCD data collection allows examination of identity development in an intersectional manner.

Early Adolescent Substance Use Before and During the COVID-19 Pandemic: A Longitudinal Survey in the ABCD Study Cohort.

PURPOSE: Evaluate changes in early adolescent substance use during the coronavirus disease 2019 (COVID-19) pandemic using a prospective, longitudinal, nationwide cohort. METHODS: Participants were enrolled in the Adolescent Brain Cognitive Development Study. A total of 7,842 youth (mean age = 12.4 years, range = 10.5-14.6) at 21 study sites across the U.S. completed a three-wave assessment of substance use between May and August 2020. Youth reported whether they had used alcohol, nicotine, cannabis, or other substances in the past 30 days. Data were linked to prepandemic surveys that the same youth had completed in the years 2018-2020, before the advent of the COVID-19 pandemic. RESULTS: Past-30-day substance use remained stable in the 6 months since stay-at-home orders were first issued in U.S. states/counties; was primarily episodic (1-2 days in the past month); and was typically limited to a single substance. Using pretest/posttest and age-period designs, we found that compared to before the pandemic, fewer youth were using alcohol and more youth were using nicotine or misusing prescription drugs. During the pandemic, youth were more likely to use substances when they were more stressed by pandemic-related uncertainty; their family experienced material hardship; their parents used alcohol or drugs; or they experienced greater depression or anxiety. Neither engagement in social distancing nor worry about COVID-19 infection was associated with substance use. Several risk factors were stronger among older (vs. younger) adolescents. CONCLUSIONS: Among youth in early adolescence, advent of the COVID-19 pandemic was associated with decreased use of alcohol and increased use of nicotine and misuse of prescription drugs.

Replication Stress Induces Global Chromosome Breakage in the Fragile X Genome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene and deficiency of a functional FMRP protein. FMRP is known as a translation repressor whose nuclear function is not understood. We investigated the global impact on genome stability due to FMRP loss. Using Break-seq, we map spontaneous and replication stress-induced DNA double-strand breaks (DSBs) in an FXS patient-derived cell line. We report that the genomes of FXS cells are inherently unstable and accumulate twice as many DSBs as those from an unaffected control. We demonstrate that replication stress-induced DSBs in FXS cells colocalize with R-loop forming sequences. Exogenously expressed FMRP in FXS fibroblasts ameliorates DSB formation. FMRP, not the I304N mutant, abates R-loop-induced DSBs during programmed replication-transcription conflict. These results suggest that FMRP is a genome maintenance protein that prevents R-loop accumulation. Our study provides insights into the etiological basis for FXS.

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Increasing Compliance with a New Interunit Handoff Process: A Quality Improvement Project.

INTRODUCTION: Current literature demonstrates that standardizing interunit patient handoff improves communication, information transfer, and patient safety. However, few studies have focused on increasing staff compliance with new handoff processes. The purpose of this quality improvement project was to incorporate both user input into process design and on-the-job coaching with a newly introduced nurse handoff process between the postanesthesia care unit and Medical/Surgical units. We hypothesized that staff compliance would be 100% within 90 days. METHODS: The team's intervention consisted of (1) involving representative frontline nursing staff in the standardization and modification of the handoff process and (2) providing on-the-job coaching as the new process was being trialed at the bedside. We designed the handoff process during a 2-day workshop and a 1.5-week pilot. Data included the number of observed noncompliant process elements and handoff duration. Three sequential 30-day plan-do-study-act cycles were followed, during which compliance observations and user feedback were used to refine the design and coaching iteratively. RESULTS: A total of 1,800 process elements were observed and coached throughout a 90-day trial period. The number of observed noncompliant elements decreased from 15% (92) to 4% (22) from the first 30-day interval to the final 30-day interval. There was no undesirable increase in handoff duration (mean, 8.05 ± 4.72 minutes), and several potential errors-related to orders, charting, and patient placement-were prevented by using the new handoff. CONCLUSIONS: User input and on-the-job coaching resulted in iteratively increasing frontline compliance with a new standardized handoff process.

Stress exposures, neurodevelopment and health measures in the ABCD study.

The Adolescent Brain Cognitive Development (ABCD) Study, a large, longitudinal study of brain development and child health, is uniquely positioned to explore relationships among stress, neurodevelopment, and psychiatric symptomatology, including substance use and addiction. There is much we do not know about how adverse experiences affect the developing brain and cognitive, social, emotional, and academic outcomes. The data collected by the ABCD Study will allow the examination of the relationships among these variables in adolescence, including the effects of stressors (e.g., abuse, neglect, household challenges, parental substance use) on psychological adjustment and other stress responses. A comprehensive protocol that includes physical and mental health, substance use, culture and environment, neurocognitive assessments, biospecimen analyses, and structural and functional neuroimaging will provide opportunities for learning about the impacts of stressors on health and other outcomes in the context of adolescent development. This knowledge could lead to the development of interventions that reduce or even reverse the impacts of stressors.

Effect of oral trazodone on the minimum alveolar concentration of isoflurane in dogs.

OBJECTIVE: To determine the effect of oral trazodone on the minimum alveolar concentration (MAC) of isoflurane in dogs. STUDY DESIGN: Prospective blinded, single-observer, randomized crossover experimental study. ANIMALS: Six adult (age 6.8 ± 1.6 months) healthy dogs (three males and three females), weighing 24.8 ± 3.4 kg (mean ± standard deviation). METHODS: Each dog was anesthetized twice with a minimum of 7 days between anesthetic episodes. Dogs were randomly assigned to be administered two treatments in a crossover design: premedication with trazodone (8 mg kg-1; TRAZ-ISO) orally 2 hours prior to an anesthetic episode or no (ISO). Dogs were anesthetized with intravenous propofol (6 mg kg-1) and isoflurane in >95% oxygen. Isoflurane MAC was determined using an iterative bracketing technique with electrodes placed in the buccal mucosa. Hemodynamic variables were compared at the lowest end-tidal isoflurane concentration at which each dog did not respond. A paired t test was used to assess the effect of treatment on outcome variables with significance set to a value of p < 0.05. RESULTS: The MAC concentration (mean ± standard deviation) in dogs administered TRAZ-ISO was 0.85 ± 0.17% compared with 1.02 ± 0.11% in those administered ISO (p = 0.01, 95% confidence interval -0.25 to -0.05), resulting in a mean MAC reduction of 17 ± 12%. There were no differences in hemodynamic variables between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Premedication of dogs with oral trazodone (8 mg kg-1) 2 hours prior to anesthetic induction has a significant isoflurane MAC sparing effect with no significant observed hemodynamic benefit.

An Improved Method for Measuring Chromatin-binding Dynamics Using Time-dependent Formaldehyde Crosslinking.

Formaldehyde crosslinking is widely used in combination with chromatin immunoprecipitation (ChIP) to measure the locations along DNA and relative levels of transcription factor (TF)-DNA interactions in vivo. However, the measurements that are typically made do not provide unambiguous information about the dynamic properties of these interactions. We have developed a method to estimate binding kinetic parameters from time-dependent formaldehyde crosslinking data, called crosslinking kinetics (CLK) analysis. Cultures of yeast cells are crosslinked with formaldehyde for various periods of time, yielding the relative ChIP signal at particular loci. We fit the data using the mass-action CLK model to extract kinetic parameters of the TF-chromatin interaction, including the on- and off-rates and crosslinking rate. From the on- and off-rate we obtain the occupancy and residence time. The following protocol is the second iteration of this method, CLKv2, updated with improved crosslinking and quenching conditions, more information about crosslinking rates, and systematic procedures for modeling the observed kinetic regimes. CLKv2 analysis has been applied to investigate the binding behavior of the TATA-binding protein (TBP), and a selected subset of other TFs. The protocol was developed using yeast cells, but may be applicable to cells from other organisms as well.

Outreach and innovation: Communication strategies for the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study, a large, longitudinal study of brain development and child health, relies on the engagement of communities, educators, and families to ensure its success. To that end, community and partner relationships, development of targeted messages and materials for specific audiences (educators, families, youth, scientists), and continued and consistent outreach must be an integral part of the Consortium activities. The ABCD Consortium has made these efforts a priority and developed a framework to raise awareness about the study and promote sustained broad-base support from diverse stakeholders.

Second-generation method for analysis of chromatin binding with formaldehyde-cross-linking kinetics.

Formaldehyde-cross-linking underpins many of the most commonly used experimental approaches in the chromatin field, especially in capturing site-specific protein-DNA interactions. Extending such assays to assess the stability and binding kinetics of protein-DNA interactions is more challenging, requiring absolute measurements with a relatively high degree of physical precision. We previously described an experimental framework called the cross-linking kinetics (CLK) assay, which uses time-dependent formaldehyde-cross-linking data to extract kinetic parameters of chromatin binding. Many aspects of formaldehyde behavior in cells are unknown or undocumented, however, and could potentially affect CLK data analyses. Here, we report biochemical results that better define the properties of formaldehyde-cross-linking in budding yeast cells. These results have the potential to inform interpretations of "standard" chromatin assays, including chromatin immunoprecipitation. Moreover, the chemical complexity we uncovered resulted in the development of an improved method for measuring binding kinetics with the CLK approach. Optimum conditions included an increased formaldehyde concentration and more robust glycine-quench conditions. Notably, we observed that formaldehyde-cross-linking rates can vary dramatically for different protein-DNA interactions in vivo Some interactions were cross-linked much faster than the in vivo macromolecular interactions, making them suitable for kinetic analysis. For other interactions, we found the cross-linking reaction occurred on the same time scale or slower than binding dynamics; for these interactions, it was sometimes possible to compute the in vivo equilibrium-binding constant but not binding on- and off-rates. This improved method yields more accurate in vivo binding kinetics estimates on the minute time scale.