ADHD risk genes involved in dopamine signaling and metabolism are associated with reduced estimated life expectancy at young adult follow-up in hyperactive and control children.

ADHD is associated with an elevated risk of mortality and reduced estimated life expectancy (ELE) by adulthood. Reduced life expectancy is substantially related to the trait of behavioral disinhibition; a correlate of both ADHD and of several dopamine genes related to dopamine signaling and metabolism. We therefore hypothesized that several ADHD risk genes related to dopamine might also be predictive of reduced ELE. Using a longitudinal study of 131 hyperactive children and 71 control cases followed to young adulthood, we examined whether several polymorphisms involving DRD4, DAT1, and DBH were related to ELE. The homozygous 9/9 allele of DAT1 and the heterozygous allele of DBH TaqI were associated with 5- and 2-year reductions, respectively, in total ELE. They did not operate on ELE through any relationships to ADHD specifically or behavioral disinhibition more generally. Instead, they showed links to alcohol use (DBH), reduced education, smoking, and reduced exercise (DAT1) employed in the computation of ELE. We conclude that polymorphisms of two dopamine genes are linked to reductions in ELE independently of their association with ADHD.

Commentary: One way attention-deficit/hyperactivity disorder can be life threatening? A travelogue on Nikolas et al. (2016).

I provide a brief commentary on the brilliant accompanying study of Nikolas et al. concerning risky bicyclist-automobile behavior in ADHD and typical youth. The sophistication of the simulator and procedures and the number and precision of measurements are remarkable and afford us an excellent glimpse into the specific mechanisms by which previously documented injury risk in such natural settings may be increased by ADHD in youth. I also briefly note clinically important implications of these and other research results on accident risk in ADHD.

Fluorescent protein tags affect the condensation properties of a phase-separating viral protein.

Fluorescent protein (FP) tags are extensively used to visualize and characterize the properties of biomolecular condensates despite a lack of investigation into the effects of these tags on phase separation. Here, we characterized the dynamic properties of µNS, a viral protein hypothesized to undergo phase separation and the main component of mammalian orthoreovirus viral factories. Our interest in the sequence determinants and nucleation process of µNS phase separation led us to compare the size and density of condensates formed by FP::µNS to the untagged protein. We found an FP-dependent increase in droplet size and density, which suggests that FP tags can promote µNS condensation. To further assess the effect of FP tags on µNS droplet formation, we fused FP tags to µNS mutants to show that the tags could variably induce phase separation of otherwise noncondensing proteins. By comparing fluorescent constructs with untagged µNS, we identified mNeonGreen as the least artifactual FP tag that minimally perturbed µNS condensation. These results show that FP tags can promote phase separation and that some tags are more suitable for visualizing and characterizing biomolecular condensates with minimal experimental artifacts.

Distinguishing sluggish cognitive tempo from ADHD in children and adolescents: executive functioning, impairment, and comorbidity.

Controversy continues as to whether sluggish cognitive tempo (SCT) is a subtype of attention-deficit/hyperactivity disorder (ADHD) or a distinct disorder. This study examined differences between these disorders in demographics, executive functioning (EF), impairment, and prior professional diagnoses to address the issue. There were 1,800 children 6 to 17 years of age of both sexes from various U.S. ethnic backgrounds who were divided into four groups: (a) high SCT but not ADHD (N = 41), (b) high ADHD but not SCT (N = 95), (c) high in both SCT and ADHD (N = 61), and (d) the control group (N = 1,603). Besides providing demographics, parents completed scales assessing ADHD and SCT symptoms, EF deficits, and psychosocial impairment and reported their child's history of professional diagnoses. SCT symptoms formed two distinct but interrelated factors separate from those for ADHD. SCT differed from ADHD in demographics (age, sex ratio, parental education, income). ADHD was associated with more severe and pervasive EF deficits than SCT, whereas SCT was chiefly associated with mild deficits in Self-Organization. ADHD contributed far more variance to EF deficits than did SCT. Both disorders were impairing, but ADHD was more severely and pervasively so than SCT, especially in Home-School domains; SCT was most impairing in Community-Leisure domains. Different patterns of comorbidity were evident between SCT and ADHD. SCT showed less comorbidity and was particularly associated with depression. SCT may comprise a distinct disorder from ADHD but both may coexist in 39% to 59% of cases each.

Clarifying Relations Between ADHD and Functional Impairment in Adulthood: Utilization of Network and Machine Learning Approaches.

Using network analysis and random forest regression, this study identified attention-deficit/hyperactivity disorder (ADHD) symptoms most important for indicating impairment in various functional domains. Participants comprised a nationally representative sample of 1249 adults in the United States. Bridge symptoms were identified as those demonstrating unique relations with impairment domains that, in total, were stronger than those involving other symptoms. Results suggested three inattentive (i.e., difficulty organizing; does not follow through; makes careless mistakes) and one hyperactive (difficulty engaging in leisure activities) bridge symptoms. Random forest regression results supported bridge symptoms as most important (compared to other symptoms) for predicting global and specific impairment domains. Hyperactive/impulsive symptoms appeared more strongly related to impairment in women, whereas difficulty organizing and easily distracted appeared more related to impairment in men. Clarification of bridge symptoms may help identify core characteristics of ADHD in adulthood and specify screening and intervention targets to reduce risk for related impairment.

Report of a Work Group on Sluggish Cognitive Tempo: Key Research Directions and a Consensus Change in Terminology to Cognitive Disengagement Syndrome.

OBJECTIVE: The aim of this work was 2-fold: (1) to evaluate current knowledge and identify key directions in the study of sluggish cognitive tempo (SCT); and (2) to arrive at a consensus change in terminology for the construct that reflects the current science and may be more acceptable to researchers, clinicians, caregivers, and patients. METHOD: An international Work Group was convened that, in early 2021, compiled an online archive of all research studies on SCT and summarized the current state of knowledge, noted methodological issues, and highlighted future directions, and met virtually on 10 occasions in 2021 to discuss these topics and terminology. RESULTS: Major progress has been made over the last decade in advancing our understanding of SCT across the following domains of inquiry: construct measurement and stability; genetic, environmental, pathophysiologic, and neuropsychological correlates; comorbid conditions; functional impairments; and psychosocial and medication interventions. Findings across these domains are summarized, and potential avenues to pursue in the next generation of SCT-related research are proposed. Following repeated discussions on terminology, the Work Group selected "cognitive disengagement syndrome" (CDS) to replace "SCT" as the name for this construct. This term was deemed to best satisfy considerations that should apply when selecting terms for a condition or syndrome, as it does not overlap with established terms for other constructs, is not offensive, and reflects the current state of the science. CONCLUSION: It is evident that CDS (SCT) has reached the threshold of recognition as a distinct syndrome. Much work remains to further clarify its nature (eg, transdiagnostic factor, separate disorder, diagnostic specifier), etiologies, demographic factors, relations to other psychopathologies, and linkages to specific domains of functional impairment. Investigators are needed with interests and expertise spanning basic, clinical, and translational research to advance our understanding and to improve the lives of individuals with this unique syndrome.

Review: Adult Outcome as Seen Through Controlled Prospective Follow-up Studies of Children With Attention-Deficit/Hyperactivity Disorder Followed Into Adulthood.

OBJECTIVE: To describe adult outcome of people with attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood and its several key predictors via a review of 7 North American controlled prospective follow-up studies: Montreal, New York, Milwaukee, Pittsburgh, Massachusetts General Hospital (MGH), Berkeley, and 7-site Multimodal Treatment Study of Children With ADHD (MTA). METHOD: All studies were prospective and followed children with a diagnosis of ADHD and an age- and gender-matched control group at regular intervals from childhood (6-12 years of age) through adolescence into adulthood (20-40 years of age), evaluating symptom and syndrome persistence, functional outcomes, and predictors of these outcomes. RESULTS: The rates of ADHD syndrome persistence ranged from 5.7% to 77%, likely owing to varying diagnostic criteria and the source of information (self-report vs informant report) across the studies. However, all studies observed high rates of symptomatic persistence ranging from 60% to 86%. The 7 studies were largely consistent in finding that relative to control groups, research participants with childhood-diagnosed ADHD had significant impairments in the areas of educational functioning, occupational functioning, mental health, and physical health as well as higher rates of substance misuse, antisocial behavior, and unsafe driving. The most consistently observed predictors of functional outcomes included ADHD persistence and comorbidity, especially with disruptive behavior disorders. CONCLUSION: Childhood ADHD has high rates of symptomatic persistence, which is associated with negative functional outcomes. Characteristics that predict these negative outcomes, such as comorbid disruptive behavior disorders, may be important targets for intervention.

Field of daydreams? Integrating mind wandering in the study of sluggish cognitive tempo and ADHD.

In this editorial perspective, we consider the potential conceptual and empirical overlap between the research on mind wandering, particularly in its pathological extreme, and that on sluggish cognitive tempo (SCT) as it has diverged from research on attention-deficit/hyperactivity disorder. The more advanced state of research findings on the nature and correlates of mind wandering relative to that of SCT is used to suggest a variety of avenues of investigation into SCT, such as its phenomenology, positive and negative correlates, research methods, theory building, and potential to inform interventions. These and other avenues drawn from the field of mind wandering are likely to prove fruitful in further revealing the nature of SCT and its relationship to mind wandering.

Attention deficit hyperactivity disorder.

Many authors have contributed to the description of attention deficit/hyperactivity disorder (ADHD) for the two last centuries. In this chapter, we review the current diagnostic criteria, epidemiology, and history of ADHD. The different phenotypes (predominantly inattentive, predominantly hyperactive/impulsive, or combined) and diagnostic process are detailed. The DSM-5 includes the three phenotypes that begin before age 12, are present in at least two settings, and cannot be explained by another condition. Theoretical underpinnings and biological and environmental etiologies reported in the latest literature are discussed. There are many comorbidities associated with ADHD, which are associated with an increase in the negative impact on everyday life. Treatment decisions involve a complex interaction between child's age, symptom severity levels, comorbidities, functional impairments, and parents' preferences. Medication (psychostimulant and nonstimulant) and psychosocial (mainly behavioral parent training) treatments as well as school-based interventions are described.

Clarifying ADHD and Sluggish Cognitive Tempo Item Relations with Impairment: A Network Analysis.

Despite the pervasive nature of various forms of impairment associated with attention-deficit/hyperactivity disorder (ADHD), the precise nature of their associations with ADHD and related sluggish cognitive tempo (SCT), particularly at the heterogeneous item level, remains ambiguous. Using innovative network analysis techniques, we sought to identify and examine the concurrent validity of ADHD and SCT bridge items (i.e., those demonstrating the most robust relations with various forms of impairment) with respect to Overall, Home-School, and Community-Leisure impairment domains. Parents of a nationally representative sample of 1742 children (50.17% male) aged 6-17 years completed rating scales of ADHD, SCT, and impairment. Assessment of Bridge Expected Influence suggested eight bridge items primarily from impulsive and Task Completion (i.e., overlapping SCT and inattentive) domains that demonstrated relations with impairment in school performance, completing chores at home, interacting with family members, following rules, and playing sports. Sum scores only including bridge items exhibited relations with Overall, Home-School, and Community-Leisure impairment domains comparable to that of sum scores including all items. Bridge impairment areas were generally consistent across "Childhood" (6-11 years) and "Adolescence" (12-17 years). Problems listening and slowness emerged as bridge items in Childhood, whereas difficulties following through on instructions, problems waiting one's turn, and social withdrawal emerged in Adolescence. Given the comparable validity of ADHD- and SCT-related bridge items versus all items, bridge items, together, may be the most efficient indicators of impairment. Further clarification is needed across development to inform personalized assessment and intervention protocols that account for item-level heterogeneity in ADHD, SCT, and impairment phenotypes.

Engineering and combining oncolytic measles virus for cancer therapy.

Cancer immunotherapy using tumor-selective, oncolytic viruses is an emerging therapeutic option for solid and hematologic malignancies. A considerable variety of viruses ranging from small picornaviruses to large poxviruses are currently being investigated as potential candidates. In the early days of virotherapy, non-engineered wild-type or vaccine-strain viruses were employed. However, these viruses often did not fully satisfy the major criteria of safety and efficacy. Since the advent of reverse genetics systems for manipulating various classes of viruses, the field has shifted to developing genetically engineered viruses with an improved therapeutic index. In this review, we will summarize the concepts and strategies of multi-level genetic engineering of oncolytic measles virus, a prime candidate for cancer immunovirotherapy. Furthermore, we will provide a brief overview of measles virus-based multimodal combination therapies for improved tumor control and clinical efficacy.

Hyperactive Child Syndrome and Estimated Life Expectancy at Young Adult Follow-Up: The Role of ADHD Persistence and Other Potential Predictors.

OBJECTIVE: We examined if ADHD Combined Type or Presentation (ADHD-C) reduced estimated life expectancy (ELE) at young adulthood and if the persistence of ADHD to adulthood further adversely affected ELE. METHOD: A young adult follow-up of 131 hyperactive and 71 control cases was used to derive 14 variables that were entered into a life expectancy calculator to generate ELE scores. Both ratings of executive function (EF) in everyday life and tests of EF and IQ were measured along with comorbid psychopathologies. RESULTS: Childhood ADHD-C was associated with a 9.5-year reduction in healthy ELE, and a 8.4-year reduction in total ELE relative to control children by adulthood. The persistence of ADHD to adulthood was linked to a 12.7-year reduction in ELE. Several background traits accounted for more than 39% of variation in ELE. CONCLUSION: Childhood ADHD-C predicts a significantly reduced ELE by adulthood, which is further reduced by the persistence of ADHD to adult follow-up.

Time Reproduction Deficits at Young Adult Follow-Up in Childhood ADHD: The Role of Persistence of Disorder and Executive Functioning.

No studies have examined if time reproduction deficits exist in children with attention deficit hyperactivity disorder (ADHD) by adulthood. We followed 131 ADHD and 71 community control (CC) cases for 20+ years to young adulthood at which time they were given a time reproduction task. The ADHD group made smaller time reproductions and showed greater variability of errors at the longer durations compared to CC cases, whether ADHD was still present or not at follow-up. Nonverbal working memory and design fluency tests were related to timing errors while anxiety and depression were not. Childhood ADHD is associated with timing deficits at adult follow-up.

Unrecognized attention-deficit/hyperactivity disorder in adults presenting with other psychiatric disorders.

Many adults with a diagnosed psychiatric disorder also have attention-deficit/hyperactivity disorder (ADHD). In many cases, comorbid ADHD is unrecognized and/or undertreated. Differential diagnosis of adult ADHD can be challenging because ADHD symptoms may overlap with other psychiatric disorders and patients may lack insight into their ADHD-related symptoms. Current ADHD diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision may prevent appropriate diagnosis of many patients with significant ADHD symptoms. Adults may not be able to provide a history of onset of symptoms during childhood, and it may be difficult to confirm that ADHD symptoms are not better accounted for by other comorbid psychiatric conditions. Comorbid ADHD is most prevalent among patients with mood, anxiety, substance use, and impulse-control disorders. ADHD can negatively affect outcomes of other comorbid psychiatric disorders, and ADHD symptoms may compromise compliance with treatment regimens. Furthermore, unrecognized ADHD symptoms may be mistaken for poor treatment response in these comorbid disorders. In these individuals, ADHD pharmacotherapy seems to be as effective in reducing core ADHD symptoms, as it is in patients who have no comorbidity. Limited evidence further suggests that ADHD therapy may help to improve symptoms of certain psychiatric comorbidities, such as depression. Therefore, management of ADHD may help to stabilize daily functioning and facilitate a fuller recovery.

Psychosocial interventions in attention deficit hyperactivity disorder.

This brief overview of psychosocial treatment approaches to attention deficit hyperactivity disorder (ADHD) concentrates on the two that receive the greatest research support, parent training in child behavior management and teacher training in classroom management. Cognitive-behavioral training of children who have ADHD has little evidence of efficacy and group social skills training has mixed or limited evidence of effectiveness. Research should focus on more theoretically driven psychosocial treatment approaches, on potential side effects or adverse events associated with this form of intervention, and on the complex pathways that affect impairment in major life activities that could guide subsequent treatment design for such impairments.

Enhanced Control of Oncolytic Measles Virus Using MicroRNA Target Sites.

Measles viruses derived from the live-attenuated Edmonton-B vaccine lineage are currently investigated as novel anti-cancer therapeutics. In this context, tumor specificity and oncolytic potency are key determinants of the therapeutic index. Here, we describe a systematic and comprehensive analysis of a recently developed post-entry targeting strategy based on the incorporation of microRNA target sites (miRTS) into the measles virus genome. We have established viruses with target sites for different microRNA species in the 3' untranslated regions of either the N, F, H, or L genes and generated viruses harboring microRNA target sites in multiple genes. We report critical importance of target-site positioning with proximal genomic positions effecting maximum vector control. No relevant additional effect of six versus three miRTS copies for the same microRNA species in terms of regulatory efficiency was observed. Moreover, we demonstrate that, depending on the microRNA species, viral mRNAs containing microRNA target sites are directly cleaved and/or translationally repressed in presence of cognate microRNAs. In conclusion, we report highly efficient control of measles virus replication with various miRTS positions for development of safe and efficient cancer virotherapy and provide insights into the mechanisms underlying microRNA-mediated vector control.

Driving performance in patients with cancer in the head and neck region: a pilot study.

OBJECTIVE: To investigate actual driving performance in a group of patients with cancer in the head and neck region. DESIGN: A nonrandomized controlled trial. PARTICIPANTS: Ten patients with cancer in the head and neck region participated in a driving evaluation using a virtual reality driving simulator. Driving performance from the simulator and observer ratings on participants' driving behaviors were compared between a group of patients with cancer in the head and neck region and a group of 50 community control subjects. MAIN OUTCOME MEASURES: Average speed, mean brake reaction time, steering variability, the total number of (fatal and nonfatal) collisions during the 12-minute evaluation course on the driving simulator, and the score of the 18-item Simulator Driving Performance Scale. RESULTS: Using Mann-Whitney U tests, the brake reaction time and the steering variability in the cancer group were significantly longer and larger, respectively, than those in the control group (P = .04) and (P = .02). However, no significant differences were found between the 2 groups in the mean rank scores for average speed, total number of collisions, and Simulator Driving Performance Scale (P >.05 for all). CONCLUSIONS: This pilot study provides preliminary evidence indicating inferior driving performance in a group of patients with cancer in the head and neck region when compared with a community control group. Further study is needed to investigate factors attributing to the difference.

Hyperactive children as young adults: driving abilities, safe driving behavior, and adverse driving outcomes.

ADHD has been linked to poorer driving abilities and greater adverse outcomes (crashes, citations) in clinic-referred cases of teens and adults with ADHD. No study, however, has focused systematically on ADHD children followed into adulthood. The present paper does so while measuring driving-related cognitive abilities, driving behavior, and history of adverse driving outcomes. A multi-method, multi-source battery of driving measures was collected at the young adult follow-up on hyperactive (H; N=147; mean age=21.1) and community control children (CC; N=71; mean age=20.5) followed for more than 13 years. More of the H than CC groups had been ticketed for reckless driving, driving without a license, hit-and-run crashes, and had their licenses suspended or revoked. Official driving records found more of the H group having received traffic citations and a greater frequency of license suspensions. The cost of damage in their initial crashes was also significantly greater in the H than CC group. Both self-report and other ratings of actual driving behavior revealed less safe driving practices being used by the H group. Observations by driving instructors during a behind-the-wheel road test indicated significantly more impulsive errors. Performance on a simulator further revealed slower and more variable reaction times, greater errors of impulsiveness (false alarms, poor rule following), more steering variability, and more scrapes and crashes of the simulated vehicle against road boundaries in the H than in the CC group. These findings suggest that children growing up with ADHD may either have fewer driving risks or possibly under-report those risks relative to clinic-referred adults with this disorder. Deficits in simulator performance and safe driving behavior, however, are consistent with clinic-referred adults with ADHD suggesting ongoing risks for such adverse driving outcomes in children growing up with ADHD.

A review of driving risks and impairments associated with attention-deficit/hyperactivity disorder and the effects of stimulant medication on driving performance.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) may interfere with driving competence, predisposing those with the disorder to impaired driving performance and greater risk for adverse driving outcomes. Effective treatment may minimize the risk in those with ADHD. METHOD: We reviewed the scientific literature on driving risks and impairments associated with ADHD and the effects of stimulants on driving performance. Several lines of evidence were considered, including longitudinal studies and community-derived sample studies. The present review is based on a weekly review (by the first author) of all journals in the behavioral and social sciences indexed in the publication Current Contents spanning the past 15 years, as well as a search of the reference section of all studies found that pertained to driving risks associated with ADHD or to the treatment of ADHD as it relates to driving difficulties. RESULTS: The review of the scientific literature demonstrated well-documented driving risks and impairments associated with ADHD and the positive effects of stimulant medications on driving performance. CONCLUSIONS: Clinicians should educate patients/caregivers about the increased risk of adverse outcomes among untreated individuals with ADHD and the role of medication in potentially improving driving performance. IMPACT ON INDUSTRY: Owing to the significantly higher risk of adverse driving outcomes, the use of stimulant medications to treat people with ADHD who drive may reduce such safety risks.

A pilot study of the effects of atomoxetine on driving performance in adults with ADHD.

OBJECTIVE: There is a high risk of vehicular crashes, traffic citations, and poorer driving performance in adults with ADHD. This pilot study examines the value of a new nonstimulant (atomoxetine) for improving the driving performance of adults with ADHD. METHOD: Atomoxetine (1.2 mg/kg daily for 3 weeks) and a placebo are studied on 18 adults with ADHD (M age = 37 years) using ratings of ADHD symptoms, impairment, and safe driving behavior; a virtual reality driving simulator; and ratings of simulator performance. RESULTS: Atomoxetine improves self-ratings of ADHD symptoms, impairments, safe driving behavior, and simulator driving performance. No effects of atomoxetine are evident on others' ratings of driving behavior or on the simulator. Practice effects on the simulator may have obscured those drug effects. CONCLUSION: The authors find a mixed pattern of results such that atomoxetine warrants further study for its effects on driving in this high-risk population.