The Kinetochore Receptor for the Cohesin Loading Complex.

The ring-shaped cohesin complex brings together distant DNA domains to maintain, express, and segregate the genome. Establishing specific chromosomal linkages depends on cohesin recruitment to defined loci. One such locus is the budding yeast centromere, which is a paradigm for targeted cohesin loading. The kinetochore, a multiprotein complex that connects centromeres to microtubules, drives the recruitment of high levels of cohesin to link sister chromatids together. We have exploited this system to determine the mechanism of specific cohesin recruitment. We show that phosphorylation of the Ctf19 kinetochore protein by a conserved kinase, DDK, provides a binding site for the Scc2/4 cohesin loading complex, thereby directing cohesin loading to centromeres. A similar mechanism targets cohesin to chromosomes in vertebrates. These findings represent a complete molecular description of targeted cohesin loading, a phenomenon with wide-ranging importance in chromosome segregation and, in multicellular organisms, transcription regulation.

Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

Lactate regulates cell cycle by remodelling the anaphase promoting complex.

Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here we use a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we identify a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodelling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We find that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. This mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient-replete growth phase to stimulate timed opening of APC/C, cell division and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodelling and can overcome anti-mitotic pharmacology via mitotic slippage. In sum, we define a biochemical mechanism through which lactate directly regulates protein function to control the cell cycle and proliferation.

Recognition of centromere-specific histone Cse4 by the inner kinetochore Okp1-Ame1 complex.

Successful mitosis depends on the timely establishment of correct chromosomal attachments to microtubules. The kinetochore, a modular multiprotein complex, mediates this connection by recognizing specialized chromatin containing a histone H3 variant called Cse4 in budding yeast and CENP-A in vertebrates. Structural features of the kinetochore that enable discrimination between Cse4/CENP-A and H3 have been identified in several species. How and when these contribute to centromere recognition and how they relate to the overall structure of the inner kinetochore are unsettled questions. More generally, this molecular recognition ensures that only one kinetochore is built on each chromatid and that this happens at the right place on the chromatin fiber. We have determined the crystal structure of a Cse4 peptide bound to the essential inner kinetochore Okp1-Ame1 heterodimer from budding yeast. The structure and related experiments show in detail an essential point of Cse4 contact and provide information about the arrangement of the inner kinetochore.

Secondary analyses of sex differences in attention improvements across three clinical trials of a digital therapeutic in children, adolescents, and adults with ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) remains underdiagnosed and undertreated in girls. Inattentive symptoms, often predominant in girls with ADHD, represent a key driver of impairment and often persist into adulthood. AKL-T01 is a regulated digital therapeutic targeting inattention. We examined potential sex differences in the efficacy of AKL-T01 in three separate trials for 1) children, 2) adolescents, and 3) adults. METHODS: We conducted secondary analyses of clinical outcomes by sex in three AKL-T01 randomized clinical trials in ADHD (n1 = 180 children 30.6% female, M(SD) age = 9.71 (1.32); n2 = 146 adolescents; 41.1% female, M(SD) age = 14.34 (1.26); n3 = 153 adults; 69.9% female, M(SD) age = 39.86 (12.84)). Active treatment participants used AKL-T01 for 25 min/day over 4-6 weeks. Primary outcomes included change in attention on the Test of Variables of Attention (TOVA) and symptom change on the clinician-rated ADHD Rating Scale (ADHD-RS). To evaluate study hypotheses, we conducted a series of robust linear regressions of TOVA and ADHD-RS change scores by sex, adjusting for baseline scores. RESULTS: In children, girls demonstrated greater improvement in objective attention relative to boys following AKL-T01 (TOVA Attentional Composite Score; Cohen's d = .36 and Reaction Time Mean Half; Cohen's d = .54), but no significant sex differences in ADHD rating scale change. We did not observe significant sex differences in outcomes in the adolescent or adult trials. Limitations include binary sex categorization and slight study design variation across the three samples. CONCLUSION: AKL-T01 might notably improve attentional functioning in girls with ADHD relative to boys. Objective attention measures may be particularly important in the assessment of attentional improvement in childhood, given known gender biases in ADHD symptom reporting. We emphasize the importance of considering sex and gender-specific factors in ADHD treatment evaluation. TRIAL REGISTRATIONS: STARS ADHD CHILD: ClinicalTrials.gov ID NCT03649074; STARS ADHD ADOLESCENT: ClinicalTrials.gov ID NCT04897074; STARS ADHD ADULT: ClinicalTrials.gov ID NCT05183919.

Pubertal timing in adolescents with ADHD: extension and replication in an all-female sample.

Pubertal timing predicts a miscellany of negative mental and physical health outcomes. Prior work examining pubertal timing in youth with attention-deficit hyperactivity disorder (ADHD) has failed to investigate potential sex specificity of results. Therefore, we aim to extend past findings in a sample of female adolescents with ADHD. We compare pubertal timing (1) between females with and without carefully diagnosed ADHD and (2) between females with ADHD who do vs. do not have a history of stimulant medication use during childhood. We examine 127 adolescent females with childhood-diagnosed ADHD and 82 matched neurotypical peers (Mage: 14.2 years, range: 11.3-18.2) from the Berkeley Girls with ADHD Longitudinal Study (Wave 2). We measured pubertal timing using self-reported Tanner staging and age at menarche. Three strategies compared pubertal timing across groups: (1) χ 2 tests of Tanner Stages, (2) t tests of residuals of pubertal status regressed on age, and (3) t tests of age at menarche. Pubertal timing of girls with and without ADHD did not differ significantly across methods and measures. Yet females with ADHD who had received stimulant medication during childhood menstruated later than those without a stimulant history, potentially related to differences in BMI across groups. On the other hand, no significant differences between medicated vs. non-medicated participants emerged for the two Tanner staging indicators. Our findings extend prior work, suggesting that females with ADHD are developing physically at a similar time as their peers, which parallels findings from previous mixed-sex samples that did not examine effects separately by sex.

Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry.

Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules.

Developmental predictors of young adult borderline personality disorder: a prospective, longitudinal study of females with and without childhood ADHD.

BACKGROUND: Research on the precursors of borderline personality disorder (BPD) reveals numerous child and adolescent risk factors, with impulsivity and trauma among the most salient. Yet few prospective longitudinal studies have examined pathways to BPD, particularly with inclusion of multiple risk domains. METHODS: We examined theory-informed predictors of young-adult BPD (a) diagnosis and (b) dimensional features from childhood and late adolescence via a diverse (47% non-white) sample of females with (n = 140) and without (n = 88) carefully diagnosed childhood attention-deficit hyperactivity disorder (ADHD). RESULTS: After adjustment for key covariates, low levels of objectively measured executive functioning in childhood predicted young adult BPD diagnostic status, as did a cumulative history of childhood adverse experiences/trauma. Additionally, both childhood hyperactivity/impulsivity and childhood adverse experiences/trauma predicted young adult BPD dimensional features. Regarding late-adolescent predictors, no significant predictors emerged regarding BPD diagnosis, but internalizing and externalizing symptoms were each significant predictors of BPD dimensional features. Exploratory moderator analyses revealed that predictions to BPD dimensional features from low executive functioning were heightened in the presence of low socioeconomic status. CONCLUSIONS: Given our sample size, caution is needed when drawing implications. Possible future directions include focus on preventive interventions in populations with enhanced risk for BPD, particularly those focused on improving executive functioning skills and reducing risk for trauma (and its manifestations). Replication is required, as are sensitive measures of early emotional invalidation and extensions to male samples.

Longitudinal relationship between oppositional defiant disorder symptoms and attention-deficit/hyperactivity disorder symptoms in Chinese children: insights from cross-lagged panel network analyses.

Oppositional defiant disorder (ODD) and attention-deficit/hyperactivity disorder (ADHD) are two of the most common childhood mental disorders, and they have substantial comorbidity. The developmental precursor model has long been widely used to explain the mechanisms of comorbidity between ODD and ADHD, however whether it is equally effective at the symptomatic level is unclear. Therefore, this study aimed to (a) examine the stability of the ODD and ADHD comorbidity network in a longitudinal sample of high-risk children in China; and (b) examine the longitudinal relationship between the ODD and ADHD symptom networks based on a developmental precursor model. Two hundred sixty-three Chinese children aged 6 to 13 years with ODD and/or ADHD were assessed for symptoms of ODD and ADHD in two surveys conducted 1 year apart. We used data from these two time points to construct two cross-sectional networks and a cross-lagged panel network (CLPN) to explore the symptom network for comorbidity of ODD and ADHD. The analysis shows that: (1) the two cross-sectional networks are highly similar in terms of structure, existence of edges, centrality estimates, and the invariance test shows that there is no significant difference between them. The symptoms "follow through", "interrupts/intrudes", "difficulty playing quietly" and "concentration" had the highest expected influence centrality at both time points. (2) Combined with the results of the cross-sectional and cross-lagged networks, we found that "annoy" and "blame" are potential bridge symptoms between the ODD and ADHD symptom networks. The symptom "annoy" forms a reciprocal predictive relationship with "interrupts/intrudes", while "blame" unidirectionally predicts "close attention". In addition, we found that "vindictive" predicted numerous ADHD symptoms, whereas "angry" was predicted by numerous ADHD symptoms. The findings emphasize the broad predictive relationship between ODD and ADHD symptoms with each other, and that ODD symptoms may lead to activation of the ADHD symptom network and vice versa. These findings suggest that the developmental precursor model at the symptom level may partially explain the comorbidity mechanisms of ODD and ADHD, and future studies should further investigate the underlying multiple mechanisms.

Latent brain state dynamics distinguish behavioral variability, impaired decision-making, and inattention.

Children with Attention Deficit Hyperactivity Disorder (ADHD) have prominent deficits in sustained attention that manifest as elevated intra-individual response variability and poor decision-making. Influential neurocognitive models have linked attentional fluctuations to aberrant brain dynamics, but these models have not been tested with computationally rigorous procedures. Here we use a Research Domain Criteria approach, drift-diffusion modeling of behavior, and a novel Bayesian Switching Dynamic System unsupervised learning algorithm, with ultrafast temporal resolution (490 ms) whole-brain task-fMRI data, to investigate latent brain state dynamics of salience, frontoparietal, and default mode networks and their relation to response variability, latent decision-making processes, and inattention. Our analyses revealed that occurrence of a task-optimal latent brain state predicted decreased intra-individual response variability and increased evidence accumulation related to decision-making. In contrast, occurrence and dwell time of a non-optimal latent brain state predicted inattention symptoms and furthermore, in a categorical analysis, distinguished children with ADHD from controls. Importantly, functional connectivity between salience and frontoparietal networks predicted rate of evidence accumulation to a decision threshold, whereas functional connectivity between salience and default mode networks predicted inattention. Taken together, our computational modeling reveals dissociable latent brain state features underlying response variability, impaired decision-making, and inattentional symptoms common to ADHD. Our findings provide novel insights into the neurobiology of attention deficits in children.

Annual Research Review: Attention-deficit/hyperactivity disorder in girls and women: underrepresentation, longitudinal processes, and key directions.

Attention-deficit/hyperactivity disorder (ADHD) - and its underlying behavioral dimensions of inattention and hyperactivity-impulsivity - have been understudied in females. We first cover the conceptual issues of prevalence, diagnostic practices, diversity, comorbidity, and causal factors, plus forces limiting awareness of ADHD in females. After a narrative review of cross-sectional and longitudinal findings, we conclude the following. (a) Girls meet diagnostic criteria for ADHD at just under half the rates of boys, a ratio that becomes much closer to equal by adulthood. (b) Girls and women with ADHD show a predominance of inattention and associated internalizing problems; boys and men display greater levels of hyperactive-impulsive symptoms and associated externalizing problems. (c) Sex differences in ADHD symptoms and related outcomes depend heavily on the clinical versus nonreferred nature of the samples under investigation. (d) Females with ADHD experience, on average, serious impairments, with a particularly heightened risk for problems in close relationships and engagement in self-harm. (e) Clinicians may overlook symptoms and impairments in females because of less overt (but still impairing) symptom manifestations in girls and women and their frequent adoption of compensatory strategies. Our review of predictors and mediators of adult outcomes highlights (a) the potential for heterotypically continuous pathways in females with childhood ADHD and (b) developmental progressions to self-harm, intimate partner violence, unplanned pregnancy, and comorbid psychopathology. Focusing on ADHD in females is necessary to characterize causal and maintaining mechanisms with accuracy and to foster responsive interventions, as highlighted in our closing list of clinical implications and research priorities.

Paths to postsecondary education enrollment among adolescents with and without childhood attention-deficit/hyperactivity disorder (ADHD): A longitudinal analysis of symptom and academic trajectories.

We examined developmental trajectories of attention-deficit/hyperactivity disorder (ADHD) symptoms, standardized achievement, and school performance for adolescents with and without ADHD who did and did not enroll in postsecondary education (PSE; N = 749; 79% boys; 63% White, 17% non-Hispanic Black, 10% Hispanic, and 10% other ethnicities). In a multisite study (recruitment based in New York, North Carolina, Pennsylvania, California, and Quebec), participants were originally enrolled between 1994 and 1998 at ages 7 to 9.9 and followed up through 2012 (Mage = 25 at final follow-up). Adolescents who eventually enrolled in PSE had less severe symptoms, but differences were modest and trajectories were similar over time. For all adolescents, standardized achievement trajectories declined up to two thirds of a standard deviation from ages 9 to 17. By the end of high school, the average GPA of adolescents with ADHD was three quarters of a point higher for those who eventually enrolled in PSE compared to those who did not. Overall, school performance mattered more than academic achievement for understanding eventual enrollment of adolescents with ADHD.

Body Mass Indices of Girls with and without ADHD: Developmental Trajectories from Childhood to Adulthood.

OBJECTIVE: We examined the predictive relation between childhood-diagnosed ADHD and trajectories of body mass index (BMI) from childhood to adulthood in an all-female sample, accounting for socioeconomic status (SES), childhood comorbidities (e.g., depression/anxiety), and stimulant usage. Childhood executive functioning (i.e., planning, sustained attention, and response inhibition) was also evaluated as a possible predictor of BMI trajectories. METHOD: We utilized longitudinal data from a full sample of 140 girls diagnosed with ADHD in childhood and 88 comparison girls matched on age and ethnicity. Girls were 6-12 years old at the first assessment and followed prospectively for 16 years. Data were collected on their BMI and stimulant medication usage across four evaluation waves. Using latent growth curve modeling, we evaluated the BMI trajectories of girls with ADHD and the comparison sample from childhood to adulthood. RESULTS: Although there was no significant difference in initial childhood BMI, girls with ADHD increased in BMI at a significantly faster rate than comparison girls across development, even when adjusting for covariates. Significant differences in BMI first emerged in adolescence; by adulthood, 40.2% of the ADHD sample met criteria for obesity versus 15.4% of the comparison sample. When covarying ADHD diagnosis, executive functioning measures were not significantly predictive of BMI increase. Adjusting for stimulant medication usage within the ADHD sample did not alter core findings. CONCLUSIONS: We discuss health-related implications for girls with ADHD, potential underlying mechanisms, and how our findings may inform both ADHD and obesity interventions.

Latent profiles of adolescents' relationships with parents and siblings: Associations with emotional and behavioral responses during the COVID-19 pandemic.

The purpose of this study is to identify the latent profiles of Chinese adolescents' family (parent-adolescent and sibling) relationships prior to and during the COVID-19 pandemic, as well as associations between those profiles and adolescents' emotional and behavioral responses. A total of 2,305 adolescents from China aged between 10 and 18 years completed measures of parent-adolescent relationships, sibling relationships, and emotional and behavioral responses during the pandemic. Four profiles of family relationships were identified via latent profile analysis and categorized as Cohesive-Decline, Mild-Decline, Conflictual-Stable, and Indifferent-Stable. Adolescents with a Conflictual-Stable profile reported more emotional and behavioral responses compared to the other profiles. In contrast, adolescents with a Cohesive-Decline profile exhibited fewer emotional responses compared to the other profiles. Adolescents with a Mild-Decline profile had fewer emotional responses than those with an Indifferent-Stable profile. These results shed light on the patterns and consequences of family relationships during the COVID-19 pandemic and have substantial implications for interventions involving family relationships in the context of regular epidemic prevention and control.

Long-term outcomes of females with attention-deficit hyperactivity disorder: increased risk for self-harm.

Although long-term outcomes of girls with attention-deficit hyperactivity disorder are understudied, high risk for adolescent and young-adult self-harm is salient. We present data on predictors and mediators of such risk, highlighting a recent dual-process model involving trait impulsivity plus family- and peer-related contributors. We conclude with recommendations for assessment and preventive intervention.

Initial Engagement in Oral Sex and Sexual Intercourse Among Adolescent Girls With and Without Childhood Attention-Deficit/Hyperactivity Disorder.

We investigated initial engagement in oral sex and sexual intercourse, as well as number of sexual partners, among a prospectively followed sample of adolescent girls with and without a thorough childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD). Participants were adolescent girls (ages 12-19) followed longitudinally as part of a study of ADHD in females. A diverse sample of 140 girls with clinician-diagnosed ADHD (47 inattentive, 93 combined) and 88 age- and ethnicity-matched comparison girls were initially recruited and invited to partake in research summer programs. We utilized data on initial engagement in oral sex, sexual intercourse, and number of sexual partners, collected during follow-up interviews conducted 5 and 10 years after baseline participation. Girls with a childhood diagnosis of ADHD engaged in oral sex at a significantly younger age and reported nearly twice as many oral sex partners than their typically developing peers. Post hoc tests revealed that group differences were driven largely by girls with the combined presentation of ADHD (i.e., those with childhood histories of both inattention and hyperactivity/impulsivity). No significant differences emerged with respect to age of initial sexual intercourse or number of male sexual intercourse partners. In sum, adolescent girls with ADHD, particularly those with the combined presentation, were more likely to engage in oral sexual activity at a young age and with a greater number of both male and female partners. Findings highlight the need for longitudinal research that quantifies and distinguishes between various forms of sexual behavior and later reproductive and mental health outcomes.

Childhood predictors and moderators of lifetime risk of self-harm in girls with and without attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is associated with self-harm during adolescence and young adulthood, especially among females. Yet little is known about the developmental trajectories or childhood predictors/moderators of self-harm in women with and without childhood histories of ADHD. We characterized lifetime risk for nonsuicidal self-injury (NSSI), suicidal ideation (SI), and suicide attempts (SA), comparing female participants with (n = 140) and without (n = 88) childhood ADHD. We examined theory-informed childhood predictors and moderators of lifetime risk via baseline measures from childhood. First, regarding developmental patterns, most females with positive histories of lifetime self-harm engaged in such behaviors in adolescence yet desisted by adulthood. Females with positive histories of self-harm by late adolescence emanated largely from the ADHD-C group. Second, we found that predictors of NSSI were early externalizing symptoms, overall executive functioning, and father's negative parenting; predictors of SI were adverse childhood experiences and low self-esteem; and predictors of SA were early externalizing symptoms, adverse childhood experiences, and low self-esteem. Third, receiver operating characteristics analyses helped to ascertain interactive sets of predictors. Findings indicate that pathways to self-harm are multifaceted for females with ADHD. Understanding early childhood predictors and moderators of self-harm can inform both risk assessment and intervention strategies.

RDoC and Psychopathology among Youth: Misplaced Assumptions and an Agenda for Future Research.

Now over 10 years old, the Research Domain Criteria (RDoC) has gained impressive traction in the adult psychopathology literature, but enthusiasm among child and adolescent psychopathologists lags somewhat behind. We consider possible reasons why RDoC has not been embraced fully in the child and adolescent literatures. We emphasize common, interrelated, and sometimes outdated assumptions that impede scientific progress that RDoC could facilitate. Traditionally, child and adolescent psychopathologists have used behavioral syndromes as gold standards against which biological markers are validated, even though behavioral syndromes are often measured with less precision; sought to identify large main effects of single biological functions on single behavioral syndromes, thereby ignoring (even if implicitly) the overwhelming etiological complexity of psychopathology; expected 1:1 correspondencies between biological functions and behaviors, despite evidence that core biological systems subserving behavior are functionally interdependent (i.e., modulate one another); and failed to consider neurobiological mechanisms of homotypic and heterotypic comorbidity and continuity. Using examples from our work, we show how a developmental, RDoC-informed approach to externalizing behavior enriches our understanding of psychopathology. We also provide an agenda for future research, which includes calls to (1) adopt neural-systems-first approaches over disorder-first approaches when studying psychopathology, (2) eschew biological reductionism by integrating environmental risk mediators into our etiopathophysiological models, (3) integrate neural vulnerabilities into the empirical latent structure of psychopathology, and (4) replace null hypothesis significance testing with computational approaches that accommodate etiological complexity by evaluating functional dependencies among RDoC constructs, including positive valence systems (approach), negative valence systems (avoidance), and arousal/regulatory systems (self-regulation).

Adolescent Mediators of Unplanned Pregnancy among Women with and without Childhood ADHD.

We aimed to identify adolescent mediators of the significant and sizable link between childhood attention deficit/hyperactivity disorder (ADHD) and later unplanned pregnancy in our prospectively followed, all-female sample. Participants included an ethnically diverse (47% non-White) sample of women with (n = 140) and without (n = 88) childhood ADHD who were assessed 4 times across childhood, adolescence, and adulthood. Potential mediators were measured via self, parent, and teacher report on questionnaires and interviews and by objective testing. We tested 5 early adolescent variables in three domains (personality, behavioral, and academic) as components of serial mediation pathways from (a) childhood ADHD status to (b) the early adolescent putative mediator to (c) risky sexual behavior in late adolescence and finally to (d) unplanned pregnancy by early adulthood. Of these, academic achievement (indirect effect = .1339, SE = .0721), 95% confidence interval (CI) [.0350, .3225] and substance use frequency (indirect effect = .0211, SE = .0167), 95% CI [.0013, .0711] operated through late-adolescent risky sexual behavior to explain rates of unplanned pregnancy, even adjusting for the effects of age, IQ, and family socioeconomic status (SES). When these 2 indirect effects were entered simultaneously, only the pathway from childhood ADHD to low academic achievement to higher rates of risky sexual behavior to unplanned pregnancy was significant (indirect effect = .0295, SE = .0145), 95% CI [.0056, .0620]. We discuss the significance of these early adolescent mediators, particularly academic engagement, as potential intervention targets intended to reduce rates of later unplanned pregnancies among female individuals with ADHD.

Executive Functions in Girls With and Without Childhood ADHD Followed Through Emerging Adulthood: Developmental Trajectories.

Using an all-female sample, we examined trajectories of executive functioning (EF) performance from childhood through emerging adulthood-and their prediction of key emerging-adult outcomes. One hundred forty girls carefully diagnosed with attention deficit/hyperactivity disorder (ADHD) and 88 matched comparison girls were administered EF measurements assessing global EF, response inhibition, and verbal working memory during childhood (M age = 9.5 years), adolescence (M age = 14.1 years), the earliest years of adulthood (M age = 19.6 years), and the end of emerging adulthood (M age = 25.6 years). Retention rates were excellent. Hierarchical linear modeling was used to estimate growth curves for each EF measure. The linear EF slopes were then used to explore how changes in EF interacted with each participant's persistence/remission of ADHD over time to influence behavioral, emotional, and academic impairment in emerging adulthood. Although all women experienced absolute improvements in EF performance across time, women with histories of ADHD consistently lagged behind comparison women, even if their ADHD symptoms had remitted by early adulthood. However, EF performance over time did not significantly influence the link between ADHD status and (a) maternal reports of associated behavioral and emotional impairment or (b) objective measures of academic achievement. These findings indicate that EF deficits should be considered when developing and implementing treatments for ADHD through emerging adulthood. Future research should be aimed at understanding the mechanisms behind these observed trajectory differences.