Examining Patterns and Predictors of ADHD Teens' Skill-Learning Trajectories During Enhanced FOrward Concentration and Attention Learning (FOCAL+) Training.

OBJECTIVE: Examine patterns and predictors of skill learning during multisession Enhanced FOrward Concentration and Attention Learning (FOCAL+) training. BACKGROUND: FOCAL+ teaches teens to reduce the duration of off-road glances using real-time error learning. In a randomized controlled trial, teens with ADHD received five sessions of FOCAL+ training and demonstrated significant reductions in extended glances (>2-s) away from the roadway (i.e., long-glances) and a 40% reduced risk of a crash/near-crash event. Teens' improvement in limiting long-glances as assessed after each FOCAL+ training session has not been examined. METHOD: Licensed teen (ages 16-19) drivers with ADHD (n = 152) were randomly assigned to five sessions of either FOCAL+ or modified standard driver training. Teens completed driving simulation assessments at baseline, after each training session, and 1 month and 6 months posttraining. Naturalistic driving was monitored for one year. RESULTS: FOCAL+ training produced a 53% maximal reduction in long-glances during postsession simulated driving. The number of sessions needed to achieve maximum performance varied across participants. However, after five FOCAL+ training sessions, number of long-glances was comparable irrespective of when teens achieved their maximum performance. The magnitude of reduction in long-glances predicted levels of long-glances during simulated driving at 1 month and 6 months posttraining but not naturalistic driving outcomes. FOCAL+ training provided the most benefit during training to teens who were younger and had less driving experience. CONCLUSION: FOCAL+ training significantly reduces long-glances beginning at the 1st training session. APPLICATION: Providing five FOCAL+ training sessions early on during teen driving may maximize benefit.

Predicting the future of our oceans-Evaluating genomic forecasting approaches in marine species.

Climate change is restructuring biodiversity on multiple scales and there is a pressing need to understand the downstream ecological and genomic consequences of this change. Recent advancements in the field of eco-evolutionary genomics have sought to include evolutionary processes in forecasting species' responses to climate change (e.g., genomic offset), but to date, much of this work has focused on terrestrial species. Coastal and offshore species, and the fisheries they support, may be even more vulnerable to climate change than their terrestrial counterparts, warranting a critical appraisal of these approaches in marine systems. First, we synthesize knowledge about the genomic basis of adaptation in marine species, and then we discuss the few examples where genomic forecasting has been applied in marine systems. Next, we identify the key challenges in validating genomic offset estimates in marine species, and we advocate for the inclusion of historical sampling data and hindcasting in the validation phase. Lastly, we describe a workflow to guide marine managers in incorporating these predictions into the decision-making process.

Preliminary examination of ADHD inattentive and cognitive disengagement syndrome symptoms in relation to probe-caught mind-wandering during a sustained attention to response task.

OBJECTIVE: The role of mind-wandering- periods of internally-directed distractibility - among patients with attention-deficit/hyperactivity disorder (ADHD) has recently garnered attention, though few studies have assessed mind-wandering using thought probes during a sustained attention to response task (SART) or examined the possible role of cognitive disengagement syndrome (CDS) symptoms. We examined whether parent- and/or teacher-reported ADHD-inattentive (ADHD-IN) or CDS symptoms were independently associated with probe-caught mind-wandering. METHODS: Fifty-four children (ages 9-12; 35.2% female) completed a SART with thought probes inquiring about various on- and off-task thoughts, including mind-wandering and distraction. Questionnaires provided information on demographics, medication treatment, and parent- and teacher-reported ADHD-IN and CDS symptoms. Regression models were estimated separately by informant to examine whether ADHD-IN or CDS symptoms were uniquely associated with mind-wandering or distraction frequency during the SART. RESULTS: Higher teacher-reported CDS ratings, but not ADHD-IN ratings, were uniquely associated with more probe-caught mind-wandering. No significant findings related to parent-reported symptoms or probe-caught distraction were observed. CONCLUSIONS: These preliminary findings add to an emerging body of work pointing to CDS as more consistently or strongly associated than ADHD-IN with mind-wandering. Theoretical and clinical implications are discussed.

A Multi-Method Examination of Peer Functioning in Children with and without Cognitive Disengagement Syndrome.

OBJECTIVE: Cognitive disengagement syndrome (CDS) includes excessive daydreaming, mental confusion, and hypoactive behaviors that are distinct from attention-deficit/hyperactivity disorder inattentive (ADHD-IN) symptoms. A growing number of studies indicate that CDS symptoms may be associated with ratings of social withdrawal. However, it is important to examine this association in children specifically recruited for the presence or absence of CDS, and to incorporate multiple methods including direct observations of peer interactions. The current study builds on previous research by recruiting children with and without clinically elevated CDS symptoms and using a multi-method, multi-informant design including recess observations and parent, teacher, and child rating scales. METHOD: Participants were 207 children in grades 2-5 (63.3% male), including 103 with CDS and 104 without CDS, closely matched on grade and sex. RESULTS: Controlling for family income, medication status, internalizing symptoms, and ADHD-IN severity, children with CDS were observed during recess to spend more time alone or engaging in parallel play, as well as less time involved in direct social interactions, than children without CDS. Children with CDS were also rated by teachers as being more asocial, shy, and socially disinterested than children without CDS. Although children with and without CDS did not differ on parent- or self-report ratings of shyness or social disinterest, children with CDS rated themselves as lonelier than children without CDS. CONCLUSIONS: Findings indicate that children with CDS have a distinct profile of peer functioning and point to the potential importance of targeting withdrawal in interventions for youth with elevated CDS symptoms.

SARS-CoV-2 Inactivation on Hard Non-porous Airplane Cabin Material Surfaces was Limited After Exposure to Far UV-C (222 nm) Radiation.

AIMS: To test the efficacy of 222 nm Far UV-C for surface disinfection of SARS-CoV-2 on inanimate surfaces from airplane cabins. METHODS AND RESULTS: Two far ultraviolet (UV-C) irradiation light systems were evaluated for disinfection of SARS-CoV-2. Materials used for carriers (test surfaces) included polished stainless steel and used airplane materials including seatbelt latches, window dust covers, sidewall laminates, and tray tables. CONCLUSIONS: While demonstrating reasonable efficacy under some experimental conditions, the data indicated that 222 nm Far UV-C disinfection alone does not reliably provide a 3 log10 or 99.9% reduction of SARS-CoV-2 on inanimate surfaces from an airplane cabin. An Ushio (Cypress, CA) 1.7" x 2.3" Care222® 12W 222nm BI lamp module tested in triplicate at a low (⁓ 1.5 mJ cm-2), medium (⁓ 3.0 mJ cm-2), and high (⁓ 6 to 9 mJ cm-2) fluence did not provide a ≥ 3 log10 or 99.9% reduction of SARS-CoV-2. The reduction of SARS-CoV-2 was greatest on stainless steel. The result was a log10 reduction of 2.83, 1.33, 2.58, and 2.21 logs for virus samples containing saline, saline with 2.5 mg BSA, saline with 0.25 mg BSA, and artificial saliva respectively at a dosage of 5 to 9 mJ cm-2. The log10 reduction of SARS-CoV-2 in saline with 2.5 mg bovine serum albumin was lowest with 1.33 for stainless steel, 0.93 for belt latch, and 0.61 for tray table at a dosage of 5 to 6 mJ cm-2.The second UV lighting system tested was a prototype mobile wand with a built-in short-pass filtered krypton-chloride cylindrical lamp. One pass of the wand over a tray holding carriers inoculated with SARS-CoV-2 in artificial saliva at a rate of approximately 1 foot (1') per second (sec) exposed the carriers to 7.3 mJ cm-2. The log10 reductions determined for the single pass were 2.97, 3.75, 1.78, 1.91, and 1.28 logs for stainless steel, belt latch, dust cover, sidewall, and tray table respectively. Two passes of the wand generated 17.2 mJ cm-2 and resulted in log10 reductions of 4.04, 3.74, 4.24, 3.68, and 1.66 logs for stainless steel, belt latch, dust cover, sidewall, and tray table respectively. The combination of higher fluence from multiple passes of the wand, the close proximity (10 cm wand to the carrier), the exposure to elevated temperatures up to 35°C, and ozone from the bulb being blown directly onto the carriers contributed to effective viral inactivation on all surfaces except the airplane tray table. The impact of temperature and ozone on viral inactivation should be determined for future testing of the 222 nm UV-C wand.

[Formula: see text] Neurocognition in children with cognitive disengagement syndrome: accurate but slow.

Cognitive disengagement syndrome (CDS), previously termed sluggish cognitive tempo (SCT), is characterized by excessive daydreaming, mental confusion, and slowed behavior or thinking. Prior research has found inconsistent relations between CDS and neurocognition, though most studies have used small or ADHD-defined samples, non-optimal measures of CDS, and/or examined limited neurocognitive domains. Accordingly, this study examined the association of parent- and teacher-reported CDS symptoms using a comprehensive neurocognitive battery in a sample of 263 children (aged 8-12) selected with a range of CDS symptomatology. Parents and teachers provided ratings of CDS and ADHD inattentive (ADHD-IN) symptoms. Path analyses were conducted to examine CDS and ADHD-IN as unique predictors of neurocognitive functioning after covarying for age, sex, and family income. CDS symptoms were uniquely associated with slower performance across a range of cognitive domains, including verbal inhibition, rapid naming/reading, planning, divided attention, and set shifting. In contrast, ADHD-IN symptoms were uniquely associated with poorer performance on a Go/NoGo task (inhibition/distractibility), visual scanning and discrimination, and interference control. Findings from the current study, amongst the first to recruit children based on levels of CDS symptomatology, provide the strongest evidence to date that the neurocognitive phenotype of CDS is characterized by slowed cognitive processing, and add to its validity as a separate syndrome from ADHD. If replicated, these findings have implications for assessment, treatment, and school accommodations for CDS. Neuroimaging studies exploring the neurobiological basis of CDS are also needed.

Comparing the Driving Skills of Adolescents with Obstructive Sleep Apnea to Healthy Controls: The Results of a Case-Controlled Observational Study.

Auto crashes are a leading cause of death and injury among adolescents. Untreated obstructive sleep apnea (OSA) can cause sleepiness and inattention, which could negatively impact novice drivers, but OSA-related studies have focused on older drivers. This study used a driving simulator to examine whether licensed 16-19-year-old adolescents with OSA have diminished driving skills. Twenty-one adolescents with OSA and twenty-eight without OSA (both confirmed using polysomnography) completed two randomly ordered driving trials in a simulator (with induced distractions versus without). A mixed ANOVA examined the between-subjects effect of the OSA group, the within-subjects effect of the distraction condition, and the group-by-condition interaction effect on the ability to maintain lane position and the frequency of extended eye glances away from the roadway. T-tests were also used to examine group differences in reported sleepiness and inattention during daily life. The distraction task increased extended off-road glances and difficulties maintaining lane position (p < 0.001). However, adolescents with OSA did not display worse eye glance or lane position than controls and there were no significant group-by-condition interactions. Although the groups differed on polysomonographic features, there were also no significant differences in reported sleepiness or inattention. The distraction task negatively impacted both groups of adolescent drivers, but those with OSA did not fare differentially worse. Most adolescents in our study had mild OSA (median obstructive apnea-hypopnea index = 4.4), the most common form in the community. It remains possible that youth with more severe OSA would show increased driving impairment.

Executive Functioning as a Predictor of Adverse Driving Outcomes in Teen Drivers With ADHD.

OBJECTIVE: The present study examined the association between executive functioning (EF) and risky driving behaviors in teens with ADHD. METHOD: Teens diagnosed with ADHD (n = 179; Mage = 17.4 years) completed two 15-min drives in a fixed-base driving simulator. EF was assessed using parent- and self-report Behavior Rating Inventory of Executive Functioning (BRIEF-2), a temporal reproduction task, and a Go/No-Go task (GNG). Driving outcomes included known predictors of crashes: count of long (>2 s) off-road glances, standard deviation (SD) of lane position (SDLP), mean speed, and SD speed. Generalized linear mixed models, controlling for intelligence and driving experience, were conducted. RESULTS: Higher rates of GNG commission errors predicted higher rates of long off-road glances. Lower parent-rated EF and increased rates of GNG omission errors predicted SDLP. Higher rates of GNG commission errors also predicted faster average driving speed. CONCLUSION: Heterogeneity in EF is associated with differences in teen ADHD risky driving behaviors.

Examining bidirectional associations between sleep and behavior among children with attention-deficit/hyperactivity disorder.

Background: Children with attention-deficit/hyperactivity disorder (ADHD) have more sleep problems than their peers which contribute to behavioral and functional impairments. This study examines the bidirectional relationship between nightly sleep (i.e., total sleep time and sleep efficiency) and daily behavior of children with ADHD. Method: Forty-three children (ages 6-13 [mean = 9.05, 54% male, 77% medicated]) participated in a 2-week study during an ADHD Summer Treatment Program (STP). Sleep was measured with actigraphy. Behavior was assessed using STP clinical data and daily parent and counselor ratings of ADHD symptoms, oppositional defiant disorder behaviors, and emotion regulation (e.g., difficulty regulating emotional disposition and controlling emotions). We hypothesized that healthier night's sleep measured by actigraphy (i.e., sleep efficiency and total sleep time [TST]) would relate to less ADHD symptoms, less emotional dysregulation, and better academic performance the next day. Additionally, we hypothesized that less ADHD symptoms, less emotional dysregulation, and greater academic performance would relate to healthier sleep that night. Results: Higher nightly sleep efficiency was related to improved parent-ratings of ADHD the next day (R 2 = 0.04, p = 0.04) and improved parent-ratings of ADHD during the day lead to higher sleep efficiency that night (R 2 = 0.002, p = 0.02). Higher rates of daily assignment completion were related to higher sleep efficiency at night (R 2 = 0.035, p = 0.03). TST was not related to any behavioral outcomes. Conclusion: Sleep efficiency may be more relevant than TST to behavioral performance the next day. Additionally, a bidirectional relationship exists between sleep efficiency and parent ratings of ADHD. Findings highlight the importance of assessing for manifestations of poor sleep efficiency, waking minutes, and wakings after sleep onset when diagnosing and treating ADHD.

Environmental predictors of children's executive functioning development.

Executive functioning (EF) abilities develop through childhood, but this development can be impacted by various psychosocial environmental influences. Using longitudinal data from the Health Outcome and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort study, we examined if psychosocial environmental factors were significant predictors of EF development. Study participants comprised 271 children and their primary caregivers (98.5% mothers) followed from birth to age 12. We identified four distinct EF developmental trajectory groups comprising a consistently impaired group (13.3%), a descending impairment group (27.7%), an ascending impairment group (9.95%), and a consistently not impaired group (49.1%). Higher levels of maternal ADHD and relational frustration appear to be risk factors for increased EF difficulty over time, while higher family income may serve as a protective factor delaying predisposed EF impairment. Important intervention targets might include teaching positive and effective parenting strategies to mothers whose children are at risk for EF dysfunction.

Association Between Stimulant Treatment and Substance Use Through Adolescence Into Early Adulthood.

Importance: Possible associations between stimulant treatment of attention-deficit/hyperactivity disorder (ADHD) and subsequent substance use remain debated and clinically relevant. Objective: To assess the association of stimulant treatment of ADHD with subsequent substance use using the Multimodal Treatment Study of ADHD (MTA), which provides a unique opportunity to test this association while addressing methodologic complexities (principally, multiple dynamic confounding variables). Design, Setting, and Participants: MTA was a multisite study initiated at 6 sites in the US and 1 in Canada as a 14-month randomized clinical trial of medication and behavior therapy for ADHD but transitioned to a longitudinal observational study. Participants were recruited between 1994 and 1996. Multi-informant assessments included comprehensively assessed demographic, clinical (including substance use), and treatment (including stimulant treatment) variables. Children aged 7 to 9 years with rigorously diagnosed DSM-IV combined-type ADHD were repeatedly assessed until a mean age of 25 years. Analysis took place between April 2018 and February 2023. Exposure: Stimulant treatment of ADHD was measured prospectively from baseline for 16 years (10 assessments) initially using parent report followed by young adult report. Main Outcomes and Measures: Frequency of heavy drinking, marijuana use, daily cigarette smoking, and other substance use were confidentially self-reported with a standardized substance use questionnaire. Results: A total of 579 children (mean [SD] age at baseline, 8.5 [0.8] years; 465 [80%] male) were analyzed. Generalized multilevel linear models showed no evidence that current (B [SE] range, -0.62 [0.55] to 0.34 [0.47]) or prior stimulant treatment (B [SE] range, -0.06 [0.26] to 0.70 [0.37]) or their interaction (B [SE] range, -0.49 [0.70] to 0.86 [0.68]) were associated with substance use after adjusting for developmental trends in substance use and age. Marginal structural models adjusting for dynamic confounding by demographic, clinical, and familial factors revealed no evidence that more years of stimulant treatment (B [SE] range, -0.003 [0.01] to 0.04 [0.02]) or continuous, uninterrupted stimulant treatment (B [SE] range, -0.25 [0.33] to -0.03 [0.10]) were associated with adulthood substance use. Findings were the same for substance use disorder as outcome. Conclusions and Relevance: This study found no evidence that stimulant treatment was associated with increased or decreased risk for later frequent use of alcohol, marijuana, cigarette smoking, or other substances used for adolescents and young adults with childhood ADHD. These findings do not appear to result from other factors that might drive treatment over time and findings held even after considering opposing age-related trends in stimulant treatment and substance use.

ABCD_Harmonizer: An Open-source Tool for Mapping and Controlling for Scanner Induced Variance in the Adolescent Brain Cognitive Development Study.

Data from multisite magnetic resonance imaging (MRI) studies contain variance attributable to the scanner that can reduce statistical power and potentially bias results if not appropriately managed. The Adolescent Cognitive Brain Development (ABCD) study is an ongoing, longitudinal neuroimaging study acquiring data from over 11,000 children starting at 9-10 years of age. These scans are acquired on 29 different scanners of 5 different model types manufactured by 3 different vendors. Publicly available data from the ABCD study include structural MRI (sMRI) measures such as cortical thickness and diffusion MRI (dMRI) measures such as fractional anisotropy. In this work, we 1) quantify the variance attributable to scanner effects in the sMRI and dMRI datasets, 2) demonstrate the effectiveness of the data harmonization approach called ComBat to address scanner effects, and 3) present a simple, open-source tool for investigators to harmonize image features from the ABCD study. Scanner-induced variance was present in every image feature and varied in magnitude by feature type and brain location. For almost all features, scanner variance exceeded variability attributable to age and sex. ComBat harmonization was shown to effectively remove scanner induced variance from all image features while preserving the biological variability in the data. Moreover, we show that for studies examining relatively small subsamples of the ABCD dataset, the use of ComBat harmonized data provides more accurate estimates of effect sizes compared to controlling for scanner effects using ordinary least squares regression.

The Effects of Attention-Deficit/Hyperactivity Disorder Symptoms on the Association between Head Impacts and Post-Season Neurocognitive and Behavioral Outcomes.

OBJECTIVE: Having attention-deficit/hyperactivity disorder (ADHD) is a risk factor for concussion that impacts concussion diagnosis and recovery. The relationship between ADHD and repetitive subconcussive head impacts on neurocognitive and behavioral outcomes is less well known. This study evaluated the role of ADHD as a moderator of the association between repetitive head impacts on neurocognitive test performance and behavioral concussion symptoms over the course of an athletic season. METHOD: Study participants included 284 male athletes aged 13-18 years who participated in high school football. Parents completed the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) ratings about their teen athlete before the season began. Head impacts were measured using an accelerometer worn during all practices and games. Athletes and parents completed behavioral ratings of concussion symptoms and the Attention Network Task (ANT), Digital Trail Making Task (dTMT), and Cued Task Switching Task at pre- and post-season. RESULTS: Mixed model analyses indicated that neither head impacts nor ADHD symptoms were associated with post-season athlete- or parent-reported concussion symptom ratings or neurocognitive task performance. Moreover, no relationships between head impact exposure and neurocognitive or behavioral outcomes emerged when severity of pre-season ADHD symptoms was included as a moderator. CONCLUSION: Athletes' pre-season ADHD symptoms do not appear to influence behavioral or neurocognitive outcomes following a single season of competitive football competition. Results are interpreted in light of several study limitations (e.g., single season, assessment of constructs) that may have impacted this study's pattern of largely null results.

Examining reaction time variability on the stop-signal task in the ABCD study.

OBJECTIVE: Reaction time variability (RTV) has been estimated using Gaussian, ex-Gaussian, and diffusion model (DM) indices. Rarely have studies examined interrelationships among these performance indices in childhood, and the use of reaction time (RT) computational models has been slow to take hold in the developmental psychopathology literature. Here, we extend prior work in adults by examining the interrelationships among different model parameters in the ABCD sample and demonstrate how computational models of RT can clarify mechanisms of time-on-task effects and sex differences in RTs. METHOD: This study utilized trial-level data from the stop signal task from 8916 children (9-10 years old) to examine Gaussian, ex-Gaussian, and DM indicators of RTV. In addition to describing RTV patterns, we examined interrelations among these indicators, temporal patterns, and sex differences. RESULTS: There was no one-to-one correspondence between DM and ex-Gaussian parameters. Nonetheless, drift rate was most strongly associated with standard deviation of RT and tau, while nondecisional processes were most strongly associated with RT, mu, and sigma. Performance worsened across time with changes driven primarily by decreasing drift rate. Boys were faster and less variable than girls, likely attributable to girls' wide boundary separation. CONCLUSIONS: Intercorrelations among model parameters are similar in children as has been observed in adults. Computational approaches play a crucial role in understanding performance changes over time and can also clarify mechanisms of group differences. For example, standard RT models may incorrectly suggest slowed processing speed in girls that is actually attributable to other factors.

Examining the Unified Theory of Behavior Change Constructs Among Adolescents Taking Attention-Deficit/Hyperactivity Disorder Medicine: A Longitudinal Study.

OBJECTIVE: To quantitatively validate the preintention factors, behavioral intentions, and implementation factors and examine the relationships theorized by the Unified Theory of Behavior Change (UTBC) model among adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted longitudinal analyses of data from 40 adolescents with ADHD, aged 11 to 15 years old, and their parents, including self-report of UTBC constructs using standardized measures. We collected pharmacy dispensing records for adolescents for the 4 months that followed. We used bivariate correlations to examine relationships between medication continuity, behavioral intentions, preintention factors, and the implementation factors. We conducted paired sample t-tests to compare adolescent and parent responses on UTBC items. RESULTS: Adolescents (mean [standard deviation {SD}] age = 13.3 [1.2] years, 75% male, 77.5% non-Hispanic Black, 90% publicly insured) reported a mean total ADHD symptom score = 29.8/54 (SD = 10.94) and mean total impairment score = 18.7/52 (SD = 10.90) and had a mean percentage of days covered with medicine over 4 months = 0.21 (range = 0-0.97). Adolescent intention to take ADHD medicine every school day was significantly related to adolescents' subsequent medication continuity (r = 0.37, P < .05). Adolescent self-concept/image and confidence taking ADHD medicine were the most important factors related to the intention to take ADHD medicine every school day. Adolescents reported less belief and intention to take ADHD medicine and more barriers to taking ADHD medicine compared to their parents. CONCLUSION: The UTBC model shed light on factors related to subsequent medication use, providing a plausible mechanism for additional research to intervene to promote future medication continuity.

Trial of Training to Reduce Driver Inattention in Teens with ADHD.

BACKGROUND: Teens with attention deficit-hyperactivity disorder (ADHD) are at increased risk for motor vehicle collisions. A computerized skills-training program to reduce long glances away from the roadway, a contributor to collision risk, may ameliorate driving risks among teens with ADHD. METHODS: We evaluated a computerized skills-training program designed to reduce long glances (lasting ≥2 seconds) away from the roadway in drivers 16 to 19 years of age with ADHD. Participants were randomly assigned in a 1:1 ratio to undergo either enhanced Focused Concentration and Attention Learning, a program that targets reduction in the number of long glances (intervention) or enhanced conventional driver's education (control). The primary outcomes were the number of long glances away from the roadway and the standard deviation of lane position, a measure of lateral movements away from the center of the lane, during two 15-minute simulated drives at baseline and at 1 month and 6 months after training. Secondary outcomes were the rates of long glances and collisions or near-collisions involving abrupt changes in vehicle momentum (g-force event), as assessed with in-vehicle recordings over the 1-year period after training. RESULTS: During simulated driving after training, participants in the intervention group had a mean of 16.5 long glances per drive at 1 month and 15.7 long glances per drive at 6 months, as compared with 28.0 and 27.0 long glances, respectively, in the control group (incidence rate ratio at 1 month, 0.64; 95% confidence interval [CI], 0.52 to 0.76; P<0.001; incidence rate ratio at 6 months, 0.64; 95% CI, 0.52 to 0.76; P<0.001). The standard deviation of lane position (in feet) was 0.98 SD at 1 month and 0.98 SD at 6 months in the intervention group, as compared with 1.20 SD and 1.20 SD, respectively, in the control group (difference at 1 month, -0.21 SD; 95% CI, -0.29 to -0.13; difference at 6 months, -0.22 SD; 95% CI, -0.31 to -0.13; P<0.001 for interaction for both comparisons). During real-world driving over the year after training, the rate of long glances per g-force event was 18.3% in the intervention group and 23.9% in the control group (relative risk, 0.76; 95% CI, 0.61 to 0.92); the rate of collision or near-collision per g-force event was 3.4% and 5.6%, respectively (relative risk, 0.60, 95% CI, 0.41 to 0.89). CONCLUSIONS: In teens with ADHD, a specially designed computerized simulated-driving program with feedback to reduce long glances away from the roadway reduced the frequency of long glances and lessened variation in lane position as compared with a control program. During real-world driving in the year after training, the rate of collisions and near-collisions was lower in the intervention group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02848092.).

Academic functioning in children with and without sluggish cognitive tempo.

Sluggish cognitive tempo (SCT) is increasingly conceptualized as a transdiagnostic set of symptoms associated with poorer functional outcomes, although the extent to which SCT is associated with academic functioning remains unclear. This study recruited children based on the presence or absence of clinically elevated SCT symptoms, using a multi-informant and multi-method design to provide a comprehensive examination of academic functioning in children with and without clinically elevated SCT symptoms. Participants were 207 children in Grades 2-5 (ages 7-11 years; 63.3% male), including 103 with clinically elevated teacher-reported SCT symptoms and 104 without elevated SCT, closely matched on grade and sex. A multi-informant, multi-method design that included standardized achievement testing, curriculum-based measurement (CBM), grades, classroom and laboratory observations, and parent and teacher rating scales was used. Children with elevated SCT symptoms had poorer academic functioning than their peers across most domains examined. Specifically, compared to children without SCT, children with elevated SCT had significantly lower grade point average (d = 0.42) and standardized achievement scores (ds = 0.40-0.77), poorer CBM performance including lower productivity (ds = 0.39-0.51), poorer homework performance and organizational skills (ds = 0.58-0.85), and lower teacher-reported academic skills (ds = 0.63-0.74) and academic enablers (ds = 0.66-0.74). The groups did not significantly differ on percentage of time on task during classroom observations or academic enabler interpersonal skills. Most effects were robust to control of family income, medication use, and attention-deficit/hyperactivity disorder inattentive symptoms, although effects for motivation and study skills academic enablers were reduced. This study demonstrates that children with clinically elevated SCT symptoms have wide-ranging academic difficulties compared to their peers without SCT. Findings point to the potential importance of assessing and treating SCT to improve academic outcomes.

Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers.

PURPOSE: Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers. EXPERIMENTAL DESIGN: We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression. RESULTS: Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that the mechanism of sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition-induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells' sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reduced Aurora kinase inhibition-induced apoptosis, whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells. CONCLUSIONS: Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.

Evaluation of four chemotherapy regimens for treatment of advanced AIDS-associated Kaposi sarcoma in Kenya: a cost-effectiveness analysis.

BACKGROUND: The most effective treatment for advanced AIDS-associated Kaposi sarcoma is paclitaxel or pegylated liposomal doxorubicin (PLD); neither is routinely used in sub-Saharan Africa due to limited availability and high cost. We examined the clinical impact, costs, and cost-effectiveness of paclitaxel or PLD in Kenya, compared with etoposide or bleomycin-vincristine. METHODS: In this study, we use the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International Model to project clinical outcomes and costs among people living with HIV and advanced Kaposi sarcoma on antiretroviral therapy. We compared four different treatment strategies: etoposide, bleomycin-vincristine, paclitaxel, or PLD. We derived cohort characteristics and costs from the Kenyan Academic Model for Providing Access to Healthcare network, and adverse events, efficacy, and mortality from clinical trials. We projected model outcomes over a lifetime and included life expectancy, per-person lifetime costs, and incremental cost-effectiveness ratios (ICERs). We conducted budget impact analysis for 5-year total costs and did deterministic and probabilistic sensitivity analyses to evaluate the effect of uncertainty in input parameters. FINDINGS: We found that paclitaxel would be more effective than bleomycin-vincristine and would increase life expectancy by 4·2 years per person. PLD would further increase life expectancy by 0·6 years per person. Paclitaxel would be the most cost-effective strategy (ICER US$380 per year-of-life-saved compared with bleomycin-vincristine) and would remain cost-effective across a range of scenarios. PLD would be cost-effective compared with paclitaxel if its price were reduced to $100 per cycle (base case $180 per cycle). Implementing paclitaxel instead of bleomycin-vincristine would save approximately 6400 life-years and would increase the overall 5-year Kenyan health-care costs by $3·7 million; increased costs would be primarily related to ongoing HIV care given improved survival. INTERPRETATION: Paclitaxel would substantially increase life expectancy and be cost-effective compared with bleomycin-vincristine for advanced AIDS-associated Kaposi sarcoma in Kenya and should be the standard of care. PLD would further improve survival and be cost-effective with a 44% price reduction. FUNDING: US National Institutes of Health and Massachusetts General Hospital. TRANSLATION: For the Swahili translation of the abstract see Supplementary Materials section.

Sex-Dependent Effects of Chronic Microdrive Implantation on Acquisition of Trace Eyeblink Conditioning.

Neuroscience techniques, including in vivo recording, have allowed for a great expansion in knowledge; however, this technology may also affect the very phenomena researchers set out to investigate. Including both female and male mice in our associative learning experiments shed light on sex differences on the impact of chronic implantation of tetrodes on learning. While previous research showed intact female mice acquired trace eyeblink conditioning faster than male and ovariectomized females, implantation of chronic microdrive arrays showed sexually dimorphic effects on learning. Microdrive implanted male mice acquired the associative learning paradigm faster than both intact and ovariectomized females. These effects were not due to the weight of the drive alone, as there were no significant sex-differences in learning of animals that received "dummy drive" implants without tetrodes lowered into the brain. Tandem mass tag mass spectrometry and western blot analysis suggest that significant alterations in the MAPK pathway, acute inflammation, and brain derived neurotrophic factor may underlie these observed sex- and surgery-dependent effects on learning.