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.

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.

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.

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.

Dutch translation and adaptation of the Barkley Deficits in Executive Functioning Scale (BDEFS)

Abstract Background Based on his model of self-regulation and executive functions, Barkley developed a self- and other-report questionnaire (the Barkley Deficits in Executive Functioning Scale - BDEFS). The BDEFS measures deficits in executive functions as expressed in daily life activities like self-management of time, self-organization, self-restraint, self-motivation, and self-regulation of emotion. Objectives This study created and analyzed a Dutch translation and adaptation in conformance with official guidelines. Methods The Dutch and English BDEFS were completed by 25 bilingual Dutch adults to evaluate semantic correspondence. Consequently, 60 Dutch participants completed the Dutch BDEFS, Barratt Impulsiveness Scale-Eleventh edition (BIS-11) and the Dysexecutive Questionnaire (DEX) to evaluate concurrent validity and internal consistency. Results The versions demonstrated sufficient semantic equivalence and Spearman's rho of total scores was high; items mostly showed moderate-to-high correlations. Regression analysis showed no proportional bias. Internal consistency was also high. Correlations between BDEFS, BIS-11 and DEX supported concurrent validity. Discussion We conclude that a successful BDEFS translation and adaptation was created with satisfactory reliability and validity. Further research should assess the utility of the BDEFS in Dutch clinical practice.

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.

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.

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.

Early Morning Functional Impairments in Stimulant-Treated Children with Attention-Deficit/Hyperactivity Disorder Versus Controls: Impact on the Family.

OBJECTIVE: Children with attention-deficit/hyperactivity disorder (ADHD) frequently manifest early morning functional (EMF) impairments before school. We conducted a quantitative research survey to assess the impact of these EMF impairments on the family unit (caregiver, spouse/partner, and siblings). STUDY DESIGN: We developed an online survey questionnaire to collect data from 300 primary caregivers of children with ADHD and 50 primary caregivers of children who did not have ADHD. RESULTS: Although the ADHD children we surveyed were currently treated with stable doses of stimulants as their primary ADHD medication for at least 3 months, their parents reported high levels of EMF impairments in the child, which had a substantial negative effect on the emotional well-being of parents, on parents' functioning during the early morning routine, and on the level of conflict with siblings. The impact of EMF impairments on family functioning was mediated by the severity of the index child's impairments. CONCLUSIONS: EMF impairments exert a pervasive and significantly negative emotional and functional burden on not only the primary caregiver but also on the spouse/partner and siblings. This work suggests that adequate ADHD symptom control during the early morning period may be an unmet need for school-age children with ADHD being treated with stimulants. More work is needed to confirm this finding and determine the degree to which symptom control at other times of day is also an unmet need.

Atomoxetine-Related Change in Sluggish Cognitive Tempo Is Partially Independent of Change in Attention-Deficit/Hyperactivity Disorder Inattentive Symptoms.

OBJECTIVES: To evaluate effects of atomoxetine versus placebo on sluggish cognitive tempo (SCT) and determine factors affecting improvement of SCT in children with attention-deficit/hyperactivity disorder (ADHD) with dyslexia (ADHD+D) or dyslexia only. METHODS: This is a post hoc analysis of a 16-week placebo-controlled, double-blind randomized phase of a previously reported atomoxetine study in children aged 10-16 years with ADHD+D, Dyslexia-only, or ADHD-only (no placebo arm). Least squares mean changes from baseline to endpoint for atomoxetine versus placebo on the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) (Parent, Teacher, and Youth) were analyzed using analysis of covariance and multiple regression (partial R2) analyses to test contributions of ADHD and dyslexia to improvements in K-SCT scores. RESULTS: Results were examined for the three informants within the three diagnostic groups (nine outcomes). Atomoxetine treatment was associated with significant reductions from baseline in seven of the nine outcomes using the p = 0.05 significance level, appropriate for exploratory analysis. When change in ADHD symptom severity was controlled, all of the seven SCT outcomes remained significant; changes in effect sizes were minimal. Regression analyses using SCT change as the criterion found a significant contribution by inattention change only for parent report, whereas, baseline SCT severity was a significant predictor in the randomized groups with the exception of teacher report in the Dyslexia-only group. CONCLUSION: Given that controlling for change in ADHD symptoms had little effect on change in SCT scores, findings suggest that change in SCT is substantially independent of change in ADHD. By inference, SCT and its response to treatment is a partially distinct phenomenon from ADHD response. Regression analyses did not reveal global effects of inattention change on SCT change; instead, baseline SCT severity was the strongest predictor of placebo-controlled treatment effect on SCT. Atomoxetine effects on SCT appear to be best predicted by how much room for improvement exists for SCT rather than by severity or improvement in inattention. CLINICAL TRIAL REGISTRATION: NCT00607919, www.clinicaltrials.gov.

Recent longitudinal studies of childhood attention-deficit/hyperactivity disorder: Important themes and questions for further research.

What we can see from the studies included here are that most cases of attention-deficit/hyperactivity disorder (ADHD) persist from the preschool years into elementary school and on into adolescence, although trajectories vary considerably across individuals. Several studies here identified a small set of unique developmental trajectories for the symptoms of ADHD. All in all, the longitudinal studies of ADHD included here have greatly advanced our understanding of the developmental course and outcomes associated with childhood 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.

The second attention disorder? Sluggish cognitive tempo vs. attention-deficit/hyperactivity disorder: update for clinicians.

Sluggish cognitive tempo (SCT) refers to an impairment of attention in hypoactive-appearing individuals that first presents in childhood. At this time, it exists only as a research entity that has yet to debut in official diagnostic taxonomies. However, it seems likely that a constellation of characteristic features of SCT may form the criteria for a newly defined childhood disorder in the foreseeable future, provided limitations in the extant findings can be addressed by future research. Most clinicians who assess and treat cases of attention- deficit/hyperactivity disorder (ADHD) have likely seen and treated someone who falls within the parameters for SCT. This article outlines the history of SCT and reviews the current understanding of the disorder, how it is distinguishable from and similar to other attention disorders, and what future directions research and treatment may take. Based on this review and their clinical experience, the authors conjecture that SCT is probably distinct from ADHD rather than being an ADHD subtype, although there is notable overlap with the ADHD predominantly inattentive and combined presentations.