Reduced temporal and spatial stability of neural activity patterns predict cognitive control deficits in children with ADHD.

This study explores the neural underpinnings of cognitive control deficits in ADHD, focusing on overlooked aspects of trial-level variability of neural coding. We employed a novel computational approach to neural decoding on a single-trial basis alongside a cued stop-signal task which allowed us to distinctly probe both proactive and reactive cognitive control. Typically developing (TD) children exhibited stable neural response patterns for efficient proactive and reactive dual control mechanisms. However, neural coding was compromised in children with ADHD. Children with ADHD showed increased temporal variability and diminished spatial stability in neural responses in salience and frontal-parietal network regions, indicating disrupted neural coding during both proactive and reactive control. Moreover, this variability correlated with fluctuating task performance and with more severe symptoms of ADHD. These findings underscore the significance of modeling single-trial variability and representational similarity in understanding distinct components of cognitive control in ADHD, highlighting new perspectives on neurocognitive dysfunction in psychiatric disorders.

Transdiagnostic Sleep and Circadian Intervention in Youth: Long-term Follow-up of a Randomized Controlled Trial.

OBJECTIVE: This preregistered study compared the effects of the Transdiagnostic Sleep and Circadian Intervention (TranS-C) with psychoeducation (PE) about sleep, health, yoga, meditation, and outdoor appreciation activities on sleep and circadian functioning, health risk, and sleep health behaviors at long-term follow-up (LTFU), an average of 8 years following treatment. We also examined if more sleep health behaviors at LTFU were associated with better sleep and circadian functioning at LTFU and if better sleep and circadian functioning were associated with lower health risk at LTFU. METHOD: At baseline, we randomly assigned adolescents with an eveningness chronotype to TranS-C (n = 89) or PE (n = 87). Of this sample, we assessed 106 young adults (mean age at follow-up = 22.5 years; n = 55 from TranS-C; n = 51 from PE) an average of 8 years following treatment. RESULTS: Despite TranS-C (vs PE) sustaining improvement in circadian functioning through 12-month follow-up, at LTFU, there were no significant differences between the conditions on any outcome, including sleep and circadian functioning, risks in 5 health domains indexed by self-report and ecological momentary assessment, sleep health behaviors, and physical measurements. Across both conditions, measures indicating poorer sleep and circadian functioning were associated with higher health risk across multiple domains, and more sleep health behaviors were associated with lower levels of eveningness at LTFU. CONCLUSION: These results provide an important window into the influence of development on long-term outcomes for youth and raise the possibility that interventions for youth could be enhanced with a focus on habit formation. CLINICAL TRIAL REGISTRATION INFORMATION: Maintaining Behavior Change: A 6-Year Follow-up of Adolescent 'Night-owls'; https://www. CLINICALTRIALS: gov/; NCT05098782. STUDY PREREGISTRATION INFORMATION: Long-term Follow-up of Young Adults Who Received TranS-C to Modify Eveningness Chronotype in Adolescence; https://osf.io/; d5a4g. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. One or more of the authors of this paper received support from a program designed to increase minority representation in science.

ADHD Symptoms in Childhood and Big Five Personality Traits in Adolescence: A Five-Year Longitudinal Study in Girls.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental condition characterized by developmentally extreme and impairing symptoms of inattention and/or hyperactivity/impulsivity. Great interest has emerged in the ways ADHD and its underlying symptom dimensions relate to the development of personality traits. Much extant research on this topic is cross-sectional, relying on self-report measures and male samples. Herein, we present data from a prospective, longitudinal study of a socioeconomically and racially diverse sample of girls, including those with ADHD and a matched neurotypical comparison sample. We examined how parent- and teacher-reported ADHD in middle childhood relate to self-reported Big Five personality traits in adolescence. As expected, childhood ADHD diagnosis prospectively predicted lower self-reported Conscientiousness, lower Agreeableness, and higher Neuroticism in adolescence. With ADHD diagnosis covaried, Inattention (IA) predicted only low Conscientiousness, Hyperactivity/Impulsivity (HI) predicted only low Agreeableness, and neither predicted adolescent Neuroticism. An exploratory moderator analysis showed that family income moderated the effects of IA and HI on the negativity of adolescent self-descriptions of their own personalities, with more pronounced negative effects for girls in families with higher (rather than lower) income. Familial pressures to achieve in higher-income families may be linked to more pronounced negative ramifications of ADHD on personality development.

Discovery of CRBN-dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

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.

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.

A Qualitative Analysis of Perspectives on Self-directed Violence in a Prospective Longitudinal Study of Young Women With and Without Childhood ADHD.

OBJECTIVE: Non-suicidal self-directed violence (NSSDV) is a significant and growing youth public health crisis. Girls with ADHD are at increased risk of engaging in NSSDV, yet qualitative studies with this population-to better understand manifestations, motivations, and developmental course-are lacking. METHOD: We conducted semi-structured, qualitative interviews with a sub-sample of 57 young women (32 with childhood ADHD, 25 neurotypical comparisons; mean age of 27 years, part of a larger prospective longitudinal study) regarding histories and manifestations of NSSDV. RESULTS: Inductive and deductive analysis revealed several key themes, including self-perceived reasons for engaging in NSSDV (affect regulation, attention seeking, self-punishment, asserting control), impulsivity, secretiveness, and in some cases motivations for desistance. CONCLUSION: Findings underscore the importance of early education and screening, especially among high-risk clinical populations. Increased resources and supports for professionals, parents, and peers are indicated, along with countering the persistent stigma associated with ADHD and NSSDV.

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.

Systematic Review and Meta-Analysis: Clinical Utility of Continuous Performance Tests for the Identification of Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: We aimed to quantify the clinical utility of continuous performance tests (CPTs) for the diagnosis of attention-deficit/hyperactivity disorder (ADHD) compared to a clinical diagnosis in children and adolescents. METHOD: Four databases (MEDLINE, PsycINFO, EMBASE, and PubMed) were screened until January 2023. Risk of bias of included results was judged with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). We statistically pooled the area under the curve, the sensitivity, and the specificity of 3 commonly used CPTs subscales: omission/inattention, commission/impulsivity, and total number of errors/ADHD subscales (PROSPERO registration: CRD42020168091). RESULTS: A total of 19 studies using commercially available CPTs were identified. Results from up to 835 control individuals and 819 cases were combined in the summary receiver operating characteristic (ROC) curve analyses (sensitivity and specificity pooling), and up to 996 cases and 1,083 control individuals in the area under the curve (AUC) analyses. Clinical utility as measured by AUCs could be considered as barely acceptable (between 0.7 and 0.8) for the most part, with the best results for the total/ADHD score, followed by omissions/inattention, and poorest for commission/impulsivity scores. A similar pattern was found when pooling sensitivity and specificity: 0.75 (95% CI = 0.66-0.82) and 0.71 (0.62-0.78) for the total/ADHD score; 0.63 (0.49-0.75) and 0.74 (0.65-0.81) for omissions; and 0.59 (0.38-0.77) and 0.66 (CI = 0.50-0.78) for commissions. CONCLUSION: At the clinical level, CPTs as a stand-alone tool have only a modest to moderate ability to differentiate ADHD from non-ADHD samples. Hence, they should be used only within a more comprehensive diagnostic process. STUDY PREREGISTRATION INFORMATION: A systematic review of screening tools for ADHD in children and adolescents; https://www.crd.york.ac.uk/prospero/; CRD42020168091.

Parental Cognitions, Treatment Engagement, and Child Outcomes of ADHD Behavioral Treatment among Asian American Families.

Asian American (AA) families remain critically underrepresented in clinical trials for ADHD interventions. Little is known about AA families' engagement in and outcomes of behavioral treatment (BT). Comparing AA families to other minoritized (OM) families and White families, this study examined parental cognitions, treatment engagement, and child outcomes of BT for ADHD inattentive type (ADHD-I). Path analyses were conducted utilizing data from a randomized controlled trial of BT for ADHD-I (N = 199 children, ages 7-11). Racial/ethnic differences in pretreatment parental self-competence and treatment expectations were examined for AA (n = 29) compared to OM (n = 35) and White (n = 135) parents. Two additional path models were conducted to examine the relations among race/ethnicity, pretreatment parental cognitions, treatment engagement, and posttreatment child outcomes. Direct effects of race/ethnicity and parental cognitions on posttreatment child outcomes as well as their indirect effects via treatment engagement were estimated. At pretreatment, AA parents endorsed lower parental self-competence and treatment expectations compared to OM and White parents. At posttreatment, AA parents reported fewer improvements in ADHD symptoms than White parents and lower global psychosocial improvement than OM parents. For all parents, treatment expectations positively predicted parent- and observer-rated treatment engagement, which in turn predicted child global psychosocial improvement. Path analyses indicated that the relationship between treatment expectations and posttreatment child global improvement was fully mediated by treatment engagement. These findings suggest that treatment expectations impede AA parents' engagement and success in BT. Implications for cultural adaptations of BT to improve AA families' treatment experience are discussed.

Using Hot and Cool Measures to Phenotype and Predict Functional Outcomes Across Dimensions of ADHD and Typical Development in Adolescents.

Multiple pathway models propose that attention deficit hyperactivity disorder (ADHD) arises from dysfunction in separate systems comprised of a "cool" or cognitive pathway versus a "hot" or emotional/reward pathway. Interactions between these pathways and the degree of maturation may further determine functional outcomes for adolescents ranging from those diagnosed with ADHD to typical development (TD). We used a latent profile analysis on rating scales and behavioral task performance assessing emotion, irritability, impulsivity, risk-taking, future orientation, and processing speed (PS) to identify subgroups of TD adolescents and adolescents with ADHD (N = 152) based on the hot and cool pathway model. We identified four classes: 1) High-Complex Challenges; 2) Moderate-Mixed Challenges; 3) Non-Emotive Impulsivity; and 4) High Regulation and Control. A multiple pathway model of ADHD is supported with classes differing in degree of emotional lability and irritability, types of impulsivity, and ability to use future consequences to modulate impulsivity and PS. The classes differed regarding functional behavior, with the High-Complex class demonstrating the most severe functional challenges in academic-related functioning. The Moderate-Mixed class also displayed significant functional challenges but with moderate emotional lability and irritability ratings. The Non-Emotive Impulsivity class exhibited low emotionality and low irritability, yet high impulsivity with limited negative functional consequences, and was composed of a mix of ADHD and TD adolescents. Differences between classes suggest ADHD symptomatology may represent both categorical and dimensional differences. Precision health interventions may be more effective in addressing the specific challenges associated with the classes rather than a one-size-fits-all approach to treating ADHD.

Pupillary dilations in a Target/Distractor visual task paradigm and attention deficit hyperactivity disorder (ADHD).

ADHD is a neurocognitive disorder characterized by attention difficulties, hyperactivity, and impulsivity, often persisting into adulthood with substantial personal and societal consequences. Despite the importance of neurophysiological assessment and treatment monitoring tests, their availability outside of research settings remains limited. Cognitive neuroscience investigations have identified distinct components associated with ADHD, including deficits in sustained attention, inefficient enhancement of attended Targets, and altered suppression of ignored Distractors. In this study, we examined pupil activity in control and ADHD subjects during a sustained visual attention task specifically designed to evaluate the mechanisms underlying Target enhancement and Distractor suppression. Our findings revealed some distinguishing factors between the two groups which we discuss in light of their neurobiological implications.

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.

Borrowing Transcriptional Kinases to Activate Apoptosis.

Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 - 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.

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.

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.

Targeted kinase degradation via the KLHDC2 ubiquitin E3 ligase.

Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves an induced proximity between the cellular ubiquitin-conjugation machinery and a target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-like homology domain-containing protein 2 (KLHDC2), a substrate adapter protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of peptide-based ligands useful for this purpose.

When should a university student be allowed academic accommodations for attention-deficit/hyperactivity disorder? A position statement for a unified procedure for use in Brazil

In higher education, reasonable accommodations are increasingly made for students with a wide range of disabilities. However, rigorous assessment is paramount to ensure these students are supported while preventing ineligible students from gaining unfair advantages. In this context, we sought to identify under which circumstances a university student should be allowed academic accommodation for attention-deficit/hyperactivity disorder (ADHD) and to outline an evidence-based policy for use in Brazil based on the global experience. We reviewed the literature to acquire information on what documents are commonly required by disability services before accommodations for ADHD are provided (including detection of malingering) and scrutinized the eligibility criteria of leading universities worldwide. Finally, renowned experts in the field and national stakeholders were consulted. Despite an exhaustive search, we found no international standard for the assessment of students with ADHD who request academic accommodation; even renowned institutions worldwide differ in their approaches to granting accommodations on the grounds of ADHD. Therefore, we propose a unified set of nationwide criteria for Brazilian universities, which could be generalized internationally. Higher education institutions in Brazil and beyond may benefit from adoption of such criteria.

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.