This study aimed to explore the relationship between family socioeconomic status (SES) and attention deficit/hyperactivity disorder (ADHD) symptoms in preschool children and the mediating role of executive function (EF). A total of 361 parents of preschool children were surveyed using the self-reported Family Situation Questionnaire, the Child Executive Functioning Inventory, and the Child Strengths and Difficulties Questionnaire. The results revealed that (1) there were significant pairwise correlations between SES, EF and its dimensions, and ADHD, except for a non-significant correlation between SES and regulation ability; (2) after controlling for preschool children’s age and sex, SES directly predicted preschoolers’ ADHD and EF partially mediated the association between SES and ADHD; and (3) among the EF dimensions, working memory and inhibitory ability significantly mediated the association between SES and ADHD, whereas the mediating effect of regulatory ability was not significant. These results suggest that SES can affect the ADHD of preschoolers both directly and through EF, especially through working memory and inhibitory ability. This supports the family stress model and family investment model of the relationship between SES and the development of children to some extent, and provides a reference for the early prevention of ADHD in children with low SES. Attention deficit/hyperactivity disorder (ADHD) is a disorder of inattention or short attention span, hyperactivity, and impulsivity that is inappropriate for a person’s age and developmental level and is often accompanied by learning difficulties, conduct disorders, and maladjustment . It typiEcosystem theory suggests that the family is an important microsystem that plays a vital role in children’s physical and mental development . Among tH1. Preschool children from low SES families will exhibit a higher incidence of ADHD.In addition to the direct influence of SES on the children’s ADHD, some researchers have focused on the indirect mechanisms in recent years. For example, it has been found that parental involvement and family conflict play mediating roles between SES and the preschool children’s ADHD . HoweverH2. EF has a significant mediating role between SES and preschool children’s ADHD.The extant literature has mostly studied EF as a whole. However, an increasing number of studies including in cognitive neuroscience have found that different components of EF have different developmental trajectories and prefrontal cortex localizations ; therefoSecond, inhibition refers to the ability to consciously control autonomous or dominant responses. This includes the inhibitory control of behaviors that do not meet current needs or are inappropriate, primarily as a process of delaying or withholding drastic responses and making appropriate choices and reactions. Some studies have shown a significant correlation between SES and young children’s inhibitory abilities , and HolFinally, regulation is the ability to reasonably regulate arousal to achieve a goal and to control the behavioral expression of emotions in a socially acceptable manner, which requires young children to regulate their behavior, attention, arousal, and emotional expression, often in relation to motivation. It has been shown that parental education levels and family income are associated with the self-regulation of children, and that children with higher SES show higher personal behavioral regulation compared to children with lower SES . AdditioBased on the above analysis of the three dimensions of EF, this study proposes H3: There are multiple significant mediating effects of the three components of EF between family SES and ADHD in preschool children see . SpecifiH3a. Working memory has a significant mediating effect between SES and ADHD.H3b. Inhibition has a significant mediating effect between SES and ADHD.H3c. Regulation has a significant mediating effect between SES and ADHD.This study used a convenience sampling method to select young children from small, middle, and large classes in a kindergarten in Kaifeng, China. After obtaining consent from the kindergarten and parents, a questionnaire was administered to the parents of the children on a voluntary basis. After eliminating the invalid data, 361 valid responses were ultimately obtained including 109  from the small class, 123  from the middle class, and 129  from the large class. The distribution of other characteristics on the participants is shown in Family income and parental education levels were used as assessment indicators. Monthly family income was measured on a 1–5 scale. The father’s and mother’s education levels were measured using one question each on a 1–5 scale. The assessment indices were calculated by first standardizing the scores of family income and parental education levels and then summing the standard scores, with higher scores indicating higher SES.The Childhood Executive Functioning Inventory was developed by Thorell and Nyberg  and tranThe instrument selected to measure ADHD in children was the hyperactivity subscale of the Strengths and Difficulties Questionnaire, a 5-item scale with a 0–2 three-level subscale, with higher scores indicating more severe ADHD problems in children. This scale has the advantage of being rapid and efficient for screening preschool children for ADHD , and CroThe questionnaire was administered by a highly trained psychology graduate student, and the parents were asked to fill out the questionnaire in the classroom after school; the questionnaire was collected after the parents had completed it. p < 0.05.The data analysis comprised of four steps: (1) The common method bias of the questionnaire data was tested using factor analysis; (2) the characteristics and relationships of the variables were analyzed using descriptive statistics and correlation analysis; (3) the mediating effects of EF were analyzed using Hayes and Preacher’s  bias-corSince all questionnaire data in this study were obtained from parental self-reports, a Harman one-way test was conducted to control for common method bias effects, and the results showed that there were 15 factors with an eigenvalue greater than 1. The explanatory value of the first common factor was 18.43%, which was less than the threshold (40%), indicating that common method bias was not significant in this study.M) and standard deviations (SD) of the preschool children’s SES, EF and its components, and ADHD, and the inter-correlation coefficients. The results revealed bivariate correlations between all variables except for family SES, which was not correlated with the preschool children’s regulation and EF. Each dimension had correlations with ADHD. Sex and age need to be used as control variables for further statistical analyses.A further test for the differences in the mediating effect values was conducted for working memory and inhibition, which was found to be not significant. Thus, SES is mainly associated with preschool children’s ADHD through working memory and inhibitory ability.This study revealed that the SES of preschool children had a significant negative predictive effect on their ADHD, hence H1 was confirmed; that is, children with lower SES are more likely to display ADHD symptoms. This further validates the family stress model, which states that low SES increases problem behaviors in young children ,28. In aIn addition to exploring the mediating role of overall EF between SES and preschool children’s ADHD, this study further examined the multiple mediating roles of the EF dimensions between SES and ADHD. Based on previous literature, this study hypothesized that all dimensions of EF may play a mediating role in the influence of SES on preschool children’s ADHD. However, this study revealed that only working memory and inhibition partially mediated the relationship between SES and preschool children’s ADHD. Therefore, H3a and H3b were confirmed; that is, young children with low SES are more likely to exhibit poorer inhibition and working memory, which, in turn, increases their risk of ADHD. As previously mentioned, this result suggests that, on one hand, low SES families directly affect the development of the brain structure and function in young children by providing them with too few resources and too little interaction , leadingThe mediating effect of regulation between SES and preschool children’s ADHD was not significant, so H3c was not confirmed. From the results, it is clear that there was a positive association between regulation problems and ADHD, but the relationship with SES was not significant. Although this may reflect that regulation ability is not a mediating variable between SES and ADHD in young children, it may also be due to the fact that the families selected for this study were from urban areas and were mostly intermediate and higher in SES distribution. Yu et al. found that family poverty hindered the development of the children’s regulation ability . This neIn summary, this study reveals that the mediating role of the dimensions of EF between SES and preschool children’s ADHD is not consistent, which, to some extent, corroborates the need to examine the three dimensions separately. It also indicates that in studies of EF, it is important to focus on both the role of overall EF and the unique roles and functions of the three dimensions of EF. Moreover, this study revealed that preschool children with low SES may have poorer performance in working memory and inhibition, which may lead to increased severity of ADHD. Therefore, working memory and inhibition training in preschool children with low SES should be focused on when conducting interventions to reduce their risk of ADHD.This study had the following limitations. First, the EF and ADHD of preschool children in this study were assessed by interviewing the parents, reflecting the stable responses of children based on their parents’ observations over a long period of time; however, despite their ecological validity, parents lacked information on immediate performance in cognitive tasks obtained through experimental methods or clinical diagnosis. Therefore, future studies should combine parental assessment and experimental methods to facilitate a balance between the ecological and objective aspects of the study. Second, this study only used a cross-sectional design to build the mediational model; although this method can provide valuable results, it cannot account for the causal relationships among the variables. Thus, future studies should apply a follow-up or experimental design to further validate the causal relationships. Third, the measure of family SES combined family income and parental education levels into one indicator. Vrantsidis et al. argue that SES has a multidimensional structure, and its components may have different effects on EF . TherefoYoung children from families with low SES are more likely to exhibit ADHD symptoms, and EF appears to play a mediating role in the relationship between SES and ADHD. Low SES is associated with impaired inhibitory control and working memory capacities in the EF of young children, which in turn is associated with the emergence of ADHD in some children.


Attention-deficit/hyperactivity disorder (ADHD) develops in early childhood and carries lifelong impact, but early identification and intervention ensure optimal clinical outcomes. Prolonged or excessive parenting stress may be a response to infant behavioral differences antecedent to developmental disorders such as ADHD, and therefore represents a potentially valuable inclusion in routine early-life assessment. To investigate the feasibility of using routinely-collected self-reported maternal parenting stress as a risk marker for child ADHD, this study investigated the longitudinal association between maternal parenting stress from 1 to 36 months after childbirth and child ADHD in early adolescence.The sample comprised 2,638 children  from the Tokyo Teen Cohort population-based birth cohort study. Mothers recorded parenting stress five times from 1 to 36 months following childbirth in the Maternal and Child Health Handbook, a tool used for routine early-life assessment in Japan. Nine years later, mothers evaluated their child's ADHD symptoms at 12 y using the hyperactivity/inattention subscale from the Strength and Difficulties Questionnaire.p =.047, 95% CI ), 18 m  and 36 m . These associations remained after adjustment for child's sex, age in months and family income.Approximately 7.5% of parents reported that they had parenting stress at 36 m after childbirth. 6.2% of children were evaluated as above the cut-off for ADHD symptoms at 12 y. Parenting stress at 1 and 3–4 m was not associated with child ADHD symptoms at 12 y. However, child ADHD symptoms at 12 y was significantly associated with parenting stress at 9–10 m (unadjusted OR = 1.42, We identified associations between parenting stress at 9–10, 18 and 36 m after childbirth and child ADHD symptoms at 12 years old. Self-reported parenting stress data may have utility as an early indicator for ADHD risk. Participation in early-life health checks, assessment of parenting stress, and tailoring support to family needs should be promoted for early identification and intervention for ADHD. Attention-deficit/hyperactivity disorder (ADHD) is a psychological disorder impacting individuals across the lifespan, and may lead to poorer health outcomes such as depression, psychotic disorder, attempted suicide, and completed suicide –3. ApproParenting a child is often stressful for parents in general, but parenting children with developmental difficulties may be especially challenging . A previN = 3171), we investigated longitudinal associations between maternal parenting stress during the first 3 years following childbirth and child ADHD at age 12 within a community sample. To ensure clinical feasibility of potential screening, we used the Maternal and Child Health handbook (MCH), which is an already widely-adopted and routinely-used tool for infant health assessment in Japan. The MCH collects parenting stress data via a single self-report item and thus presents minimal time or response burden.In the present study, we wished to investigate whether parenting stress could be clinically useful as a broad screening method for childhood ADHD risk. Using data from the Tokyo Teen Cohort (TTC), a prospective population-based birth cohort study in Japan . Participants were also requested to report the responses recorded in their Maternal and Child Health handbook (MCH) on maternal parenting stress.The MCH handbook is a booklet distributed to newly pregnant women in Japan to facilitate routine assessment of child development and health by mothers as well as healthcare professionals . In 2018Child ADHD symptoms were assessed using the hyperactivity/inattention subscale from the parent-report Strength and Difficulties Questionnaire (SDQ) , 23 at tChild age in months , sex and socio-economic status (measured via family income) were adjusted for in analyses as potential confounders. Family income was categorized into 0–5, 5–10, and 10+ million yen per year, representing the lower, middle and upper thirds of household income distribution in Tokyo.Bivariate binomial logistic regression analysis was used to examine the association between the presence of parenting stress at 1, 3–4, 9–10, 18, and 36 m, and child ADHD symptoms at age 12. Multiple binomial logistic regression analysis adjusting for sex, age in months, and annual household income followed for the above analysis. A full information maximum likelihood (FIML) estimation procedure was adopted to handle missing data  under thOf the 3,007 households that participated the second wave (age 12) survey of the TTC study, 353 were excluded for the following reasons: did not own an MCH handbook, could not confirm whether they possessed an MCH handbook, had not responded to any items in the MCH handbook regarding parenting stress, had not reported child ADHD symptoms at age 12. Thus, the final analysis included 2,654 households (88.2%). Among the 2,654 cases, about half (52.5%) of children were boys. The mean age in months at the second survey wave was 145.9 months. 64.5% of participating households had annual household incomes below 10 million yen. Among 3,007 participants, more than 70% recorded parenting stress at all timepoints .As shown in p = 0.047, 95% CI ), 18 m  and 36 m  with increasing strength at each time point. After adjustment for child's sex, age in months, and annual household income, ADHD symptoms at age 12 remained significantly associated by parenting stress at 9–10 m , 18 m  and 36 m  while associations between parenting stress at 1 and 3–4 m and ADHD symptoms at age 12 remained insignificant.To our knowledge, this is the first study to investigate the longitudinal association between maternal parenting stress at multiple intervals from 1 to 36 months post-childbirth and child ADHD symptoms at 12 years old in a population-based birth cohort sample. Our analyses found that parenting stress at 9–10, 18 and 36 months was associated (with subsequent increasing strength) with child ADHD symptoms at 12 years old, though parenting stress at earlier time points showed no such association. This finding suggests that self-reported parenting stress from 9 months may be a useful measure for early identification of children at risk of ADHD.Our finding that parenting stress at 9–10 months associated ADHD symptoms in adolescence, with increasing strength at 18 and 36 months, raises the question of what differences emerge from 9 to 36 months in children who later develop ADHD that underlie this increase in parenting stress. Sleep disturbances between 0 and 5 years are associated with ADHD in adolescence , 30, andParenting stress is a contributor to the increased likelihood of parents of children with ADHD using harsh or negative parenting strategies , 32, whiThis study shows the utility of the MCH handbook  for early identification of ADHD risk. This builds on a recent study examining the possibility of early identification of autism via developmental delay recorded in the MCH handbook  to encouOur study has a number of strengths. First, we used a large, representative population-based birth cohort, giving substantial ecological validity to our findings and allowing us to control for common sociodemographic confounders. Using the MCH handbook gave access to parenting stress data at frequent intervals over the first 36 months. In addition, since MCH handbook data was collected concurrently with infant health check-ups, our retrospective study design avoids the problem of recall bias. However, this study also had some limitations. First, we did not have parenting stress data beyond 36 months, as the MCH handbook does not record parenting stress after this time point. As such, we were unable to determine if this trend of increasing strength of parenting stress on adolescent ADHD symptoms persists as the child ages; this would be a potentially beneficial target for future research. Second, we used parent-reported child ADHD symptoms, rather than researcher-conducted interviews, teacher ratings, or clinical diagnosis. However, the SDQ attention/hyperactivity subscale has robust psychometrics for detecting ADHD , 43, 44,In conclusion, our study found that maternal parenting stress from 9 months post-childbirth was associated with child ADHD symptoms at age 12, with increasing strength at 18 months and 36 months. Maternal parenting stress from 9 months may be an indicator of later child ADHD. This time period may be extremely valuable for early intervention to ensure optimal outcomes in families caring for a child with ADHD.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Tokyo Metropolitan Institute of Medical Science. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.AN, KE, and DS conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript, being supervised by KK, MH-H, SA, and MN. JN, SK, SF, YM, MH, KB, NO, NN, KS, and MM critically reviewed the manuscript for important intellectual content and contributed to the discussion. SY supervised the statistical analysis. All authors contributed to and have approved the final manuscript.This work was supported by Grant-in-Aid for Transformative Research Areas (21A101) and Grant-in-Aid for Scientific Research on Innovative Areas  from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This study was also supported in part by JSPS KAKENHI , JST-Mirai Program (Grant No. JPMJMI21J3); AMED (Grant No. JP17ek0109262); the UTokyo Center for Integrative Science of Human Behavior (CiSHuB); and the International Research Center for Neurointelligence (WPI-IRCN) at The University of Tokyo Institutes for Advanced Study (UTIAS). The funding source had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


These studies covered experiences of receiving a diagnosis as an adult, symptomatology of adult ADHD, skills used to adapt to these symptoms, relationships between ADHD and substance use, patients’ self-perceptions, and participants’ experiences interacting with society. Many of the ADHD symptoms reported in these studies had overlap with other psychiatric conditions and may contribute to misdiagnosis and delays in diagnosis. Understanding symptomatology of ADHD in adults may inform future diagnostic criteria and guide interventions to improve quality of life.Attention-deficit/hyperactivity disorder (ADHD) is a common condition that frequently persists into adulthood, although research and diagnostic criteria are focused on how the condition presents in children. We aimed to review qualitative research on lived experiences of adults with ADHD to characterize potential ADHD symptomatology in adulthood and provide perspectives on how needs might be better met. We searched three databases for qualitative studies on ADHD. Studies ( Attention-deficit/hyperactivity disorder (ADHD) has an estimated prevalence of 7% among adults globally . ADHD haAlthough adult ADHD is highly treatable with stimulant medication , adults Non-pharmacological interventions such as cognitive behavioral therapy (CBT) have shown promise with helping adults manage their ADHD symptoms, although such symptoms are not completely ameliorated by therapy –15. A moQualitative research may provide insight into lived experiences, and findings from such studies may direct future research into potential symptoms and therapeutic interventions. The aim of this review is to describe the current qualitative literature on the lived experiences of adults with ADHD. This review may provide insight into the symptomatology of adult ADHD, identify areas where patient needs could be better met, and define gaps in understanding.Using rapid review methodology , PubMed,Studies reporting original peer-reviewed qualitative data on the lived experience of adults with ADHD, including mixed-methods studies, were eligible for inclusion. “Adult” was defined as being 18 years of age or older; studies that included adolescent and young adult participants were only included if results were reported separately by age. Studies that included some participants without ADHD were included if results were reported separately by diagnosis. Any studies with adult participants who were exclusively reflecting on their childhood experiences with ADHD were considered outside this study’s scope, as were studies on family members, medical providers, or other groups commenting on adults with ADHD. Articles could be from any country, but needed to have been published in English. Individual case studies were not included due to concerns with generalizability.Twenty percent of titles and abstracts were screened by two reviewers for meeting the inclusion criteria. Studies were not initially excluded based on participants’ ages as many titles and abstracts did not specify age. One reviewer screened the remaining abstracts; a second reviewer screened all excluded abstracts. For full-text screening, ten articles were screened by both reviewers to ensure consistency. One reviewer screened the remaining articles; a second reviewer screened all excluded articles.Quality appraisal was completed by one reviewer using the Joanna Briggs Institute critical appraisal checklist for qualitative research . Half ofData extracted included general study characteristics and methodology, participant characteristics , study aims, and text excerpts of qualitative results. Study characteristics were entered into a Google Sheets document. PDFs of all studies were uploaded into NVivo 12, and results sections were coded using grounded theory . One revOne-hundred-and-seventy-three articles were deemed relevant in title and abstract screening. Of these, 35 were included after the full-text review . ArticleAn overview of the identified themes is described in Assessment and diagnosis of adult ADHD were reported as laborious and included prior misdiagnoses –22, lackIdentity changes were another reported finding after diagnosis, both positive and negative. Some participants reported experiencing existential questioning of their identities , 26; othConsistent with current diagnostic conceptualizations, difficulties with attention and concentration were described. These difficulties hindered completion of daily life tasks at home, school, and work , 34–37. Impulsivity was widely reported and reflected in risk-taking including reckless driving, unprotected sex, and extreme sports , 36, 43.Fewer studies described participants’ struggles with hyperactivity, such as with staying still or not being constantly busy , 34, 36.Living in chaos was often reported, whether involving internal feelings of being unsettled , or exteAlthough lacking from current diagnostic criteria, emotional dysregulation was often noted. Participants reported experiencing extreme emotional reactions to interpersonal conflicts such as terminations of romantic relationships or receiving negative feedback at work , 38, 40.Not all aspects of ADHD were perceived as negative. Impulsivity was reported by some as fun and spontaneous , 37, 45,Participants reported compensatory organizational strategies that increased structure in their daily lives. Creating regimented sleeping, eating, working, and relaxing schedules , 44, 46,Participants reported being able to adjust their environment to best suit their needs, whether that be decreasing distracting stimulation , 46 or cSubstance use was also described as a coping strategy, although there were also drawbacks associated with using substances. Such findings are discussed under “substance use.”Stimulant medications were commonly used to help manage ADHD symptoms; participants reported that stimulants facilitated task prioritization, goal achievement, and productivity often to “life-changing” extents , 46–48. Participant ambivalence or hesitation to take stimulants was reported due to therapeutic and adverse effects. Reported adverse effects included “not feeling like oneself,” resulting in difficulties with socializing and creativity , 40, 47,Studies noted participants adapting to living with their symptoms by receiving formal accommodations at work and school. Reported workplace accommodations included reduction of auditory distractions and bosses who would provide organizational advice or extra reminders about due dates , 25, 40.Individual therapy was reported as helpful for managing symptoms and acquiring self-knowledge, especially therapeutic interventions designed for ADHD and CBT , 27, 41.In some studies, participants expressed desires to be involved with support groups for adults with ADHD in order to learn new coping skills and find community, but not knowing where to access such services , 40. ThoThe SUDs were commonly reported among adults with ADHD and often seen as a form of self-medication. In every study that discussed self-medication, participants reported using substances to feel calm and relaxed; substances included nicotine/tobacco, alcohol, marijuana, cocaine, and methamphetamine , 50–52. The tendencies of people with ADHD to make impulsive decisions were suggested as linking ADHD and substance use , 52. SubAlthough discontinuing substance use was regarded as a difficult process with frequent relapses, participants considered their quality of life to improve after quitting , 44, 53.Findings relating stimulant use and use of other substances were mixed. Prescription stimulant usage was reported as a protective factor against use of other substances. Participants who had previously been self-medicating reported that when they had been on stimulants, they did not need other substances to help them feel calm and focused , 50, 52.Some participants reported stimulant prescriptions as increasing risk of substance use. Some reported that stimulants directly increased nicotine cravings . IndirecParticipants often reported experiencing low self-esteem which they attributed to feeling unable to keep up with work or school, being told they were not good enough by others, and frequently failing at life goals , 41, 43.Some participants viewed ADHD as a personality trait or difference as opposed to a disorder or disability , 41, 45.Difficulties building and maintaining relationships with others were regularly reported. Participants reported that impulsivity hindered their social interactions due to their tendencies to make inappropriate remarks, engage in reckless behaviors, and agree to engagements without thinking through consequences, resulting in being associated with people to whom they did not want to be linked , 36, 43.Feeling different from others was widely reported, most notably in childhood , 31, 32.Participants with ADHD who also had children diagnosed with ADHD reported that their approaches to their children’s diagnoses were shaped by their own ADHD experiences. Parents reported uniform support of diagnostic testing, although the best time for testing was not agreed-upon , 48. OpiParticipants reported their social networks often expressed preconceived notions about the diagnosis, such as ADHD being “fake” or restricted to children , 37, 41.Some studies discussed participants’ difficulties with meeting societal expectations. Participants reported struggling to keep up with daily tasks such as maintaining their living spaces, paying bills and remembering to eat , 35, 41.Academic underachievement was widely reported; most studies focused on postsecondary education. Some participants reported having to try harder than their peers for the same results , 35, whiOccupational struggles were commonly reported, with many studies detailing participant underemployment or unemployment and high job-turnover rates , 41, 43.Adults described difficulties accessing healthcare for ADHD. Most reported having to fight to receive a diagnosis and medication due to perceptions of stigma from physicians about adult ADHD . After dThis review characterizes the current literature on the lived experiences of adults with ADHD. This includes experiences of having been diagnosed as an adult, symptomatology of adult ADHD, skills used to adapt to ADHD symptoms, relationships between ADHD and substance use, individual perceptions of self and of having received ADHD diagnoses, and social experiences interacting in society.Similar themes were noted in a previous review on lived experiences of adults with ADHD consisting of ten studies, three of which were included here . Such thThe relationship between ADHD effects and poor occupational performance has been previously described. People with ADHD often struggle with unemployment and underemployment and functional impairment at work –58. The per se. This notion builds on previous clinical observations  and stimulant use being association with SUDs. From a clinical perspective, both points will be important to understand better. With regard to the latter, ADHD and SUDs frequently co-occur; one meta-analysis found that 23% of people with SUDs met criteria for ADHD . FurtherThis review highlights gaps in the qualitative literature on adult ADHD. Nearly all included studies took place in Europe, North America or Asia; there is a dearth of qualitative research on ADHD in the Global South. Although most studies did not report race, those that did often had a majority of White participants. Racial/ethnic disparities in ADHD diagnosis may contribute to the relatively low diversity of study participants , and sucFuture qualitative studies should explore how ADHD symptoms change over the lifespan as this was not addressed in any of the included studies. There were very few findings relating to how adults with ADHD conceptualize the condition and how their diagnosis interacts with their identities. Some studies reported on difficulties adults with ADHD have with accessing services; further exploration is needed into how the medical community can better meet the needs of this population. Findings from this review may be used to inform future ADHD screening tools. The Adult ADHD Self-Report Scale (ASRS) is a widely used screening tool that covers symptoms of inattention, impulsivity, and hyperactivity . This reThis study has limitations. Being a rapid review, it was not an exhaustive search of the available literature and may have missed some relevant studies that would have been identified by a systematic search. The search strategy consisted of ADHD and qualitative research methods; studies that did not include “qualitative” in their titles or abstracts may not have been identified. This may explain why the previous review on the lived experiences of adults with ADHD  includedAttention-deficit/hyperactivity disorder is a relatively common diagnosis among adults. Exploration of the lived experiences of adults with ADHD may illuminate the breadth of symptomatology of the condition and should be considered in the diagnostic criteria for adults. Understanding symptomatology of adults with ADHD and identifying areas of unmet need may help guide intervention development to improve the quality of life of adults with ADHD.CG and MP contributed to the conception of the review. CG and GM-G performed the abstract and full text screening. CG performed the data synthesis and wrote the first draft of the manuscript. GM-G, GA, KB, and MP contributed to the revising and editing the manuscript. All authors read and approved the submitted version.


We performed correlation analysis to investigate the relation between ADHD/ASD symptoms and creativity measures. In a second phase of analysis, data from an adult ADHD case-control study (n = 151) were added to investigate the association between ADHD symptoms and divergent thinking in individuals with and without a diagnosis of ADHD.Previous research on ADHD and ASD has mainly focused on the deficits associated with these conditions, but there is also evidence for strengths. Unfortunately, our understanding of potential strengths in neurodevelopmental conditions is limited. One particular strength, creativity, has been associated with both ADHD and ASD. However, the distinct presentations of both conditions beg the question whether ADHD and ASD associate with the same or different aspects of creativity. Therefore, the current study investigated the links between ADHD and ASD symptoms, creative thinking abilities, and creative achievements. To investigate the spectrum of ADHD and ASD symptoms, self-reported ADHD and ASD symptoms, convergent (Remote Associations Test) and divergent thinking (Alternative Uses Task) and creative achievements (Creative Achievement Questionnaire) were assessed in a self-reportedly healthy sample of adults , but not for convergent thinking. Individuals with an ADHD diagnosis in the case-control sample also scored higher on measures of divergent thinking. Combining data of the population based and case-control studies showed that ADHD symptoms predict divergent thinking up to a certain level of symptoms. No significant associations were found between the total number of ASD symptoms and any of the creativity measures. However, explorative analyses showed interesting links between the ASD subdomains of problems with imagination and symptoms that relate to social difficulties. Our findings showed a link between ADHD symptoms and divergent thinking abilities that plateaus in the clinical spectrum of symptoms. For ASD symptoms, no relation was found with creativity measures. Increasing the knowledge about positive phenotypes associated with neurodevelopmental conditions and their symptom dimensions might aid psychoeducation, decrease stigmatization and improve quality of life of individuals living with such conditions. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are among the most common neurodevelopmental conditions. ADHD has a prevalence of around 5–7.8% in childhood and 1.2–7.3% in adulthood and ASD has a prevalence of around 1–2.8% in childhood and 2.5–3.4% in adulthood  with theBesides negative consequences, ADHD and ASD diagnosis and associated symptoms may not only lead to impairments alone but there might also be associated behavioral and/or cognitive strengths. Therefore, recent qualitative studies have examined self-reported strengths of ADHD and ASD –29. ExamCreativity is a broad concept. It can be defined by inventiveness and originality  resultinWhile creativity is a self-reported strength in both ADHD and ASD, the relation with the conditions might not be comparable. In fact, research on the different cognitive profiles of ADHD and ASD points to the possibility that the relation between ADHD and ASD symptoms with creativity may be more complex and non-linear than was previously assumed. An important aspect to be considered is that interindividual differences in cognitive profiles are associated with distinct creativity profiles . CognitiFor ADHD, there is more evidence for a link with stronger divergent thinking than with convergent thinking abilities . HoweverCompared to the situation in ADHD, the cognitive profile of ASD might be more beneficial for tasks that require convergent thinking. The cognitive profile of individuals with ASD is characterized with superior local processing and attention to detail –71, poorAn optimal way to investigate whether ADHD and ASD are associated with distinct types of creative thinking is to study creative thinking and (symptoms of) ADHD and ASD in the same sample. Interindividual variability in severity and/or type of symptoms is often overlooked in traditional study designs comparing two categorical groups, which leads to an important loss of depth and detail in the data and subsequent results. Because ADHD and ASD symptoms are distributed in the general population in a continuous manner, a population sample allows for an investigation of the link between ADHD/ASD symptoms, creative thinking, and creative achievements in the same sample, also preventing interference of the deficits that are associated with a clinical diagnosis. Additionally, previous creativity research made use of a variety of tasks measuring different constructs and domains, which makes it hard to draw conclusions . In ordeThe current study is based on data that were collected as part of the Brain Imaging Genetics (BIG) project , 83. TheTo deepen our understanding of the link between ADHD and divergent thinking, we used data from the IMpACT2-NL sample, an adult ADHD case-control sample (79 cases and 72 controls). In this study the same instruments as in the BIG study were used to assess creativity, but a different instrument was used to assess ADHD symptoms, see below. For a description of the IMpACT2-NL sample and the study procedures, please see the th edition (DSM-IV)  , 85. For(DSM-IV) . In the (DSM-IV) . The varTo assess ASD symptoms the participants filled out the AQ18 questionnaire . In shoruse as a bookstand, or use as a paperweight. Responses were scored on three different outcome measures of divergent thinking: 1) fluency reflects the number of non-redundant responses, 2) flexibility reflects the number of conceptual categories the responses belong to , and 3) originality reflects how novel and uncommon the ideas are . For each item, two trained coders (MB&MH) counted all ideas to determine fluency and coded all ideas to determine flexibility and originality. Cohen's Kappa was calculated per item  to assess the overlap between the category scores (flexibility) made by the two raters. The overlap between category scores (flexibility) of the two raters was sufficient . Additionally, the intraclass correlation coefficient to compare the originality scores of the two raters for each individual idea was found to be sufficient  was used to assess divergent thinking abilities . Particicoffee”. There is only one correct answer for the individual items. The total scores were calculated as the number of correctly solved items, with a range of 0 to 30. The RAT has been found to have good internal consistency  and convergent validity with other convergent thinking tasks .I have won a national prize in the field of x”, please see the example in the Creative achievements were measured with the Creative Achievement Questionnaire . This ieff correction to adjust for multiple testing. The Meff takes into account the correlation structure of the variables in the model and calculates the effective number of independent variables  and divergent thinking  scores, controlling for age and sex. We used a Mariables . For oureff calculation: CAQ total score, CAQ science/interventions score, CAQ expressive score, and CAQ performance score. The effective number of independent variables was found to be 3, leading to a corrected significance threshold of p = 0.017.To investigate if ASD/ADHD symptoms and subscales were related to creative achievements, we investigated partial correlations of ASD/ADHD total scores with scores on the creative achievements questionnaire (CAQ), controlling for age and sex. To determine the level of statistical significance, we included four variables in the MTo increase our understanding of the suggested differential relationship between ADHD symptoms and divergent thinking in people with an ADHD diagnosis versus people without an ADHD diagnosis, we combined the BIG and IMpACT2 datasets to show the entire distribution of divergent thinking scores across the full continuum of ADHD symptoms, from none in participants from the BIG study and controls from the IMpACT2-NL study) to the highest scores in individuals with an ADHD diagnosis . In comparison, the correlations between the different constructs of creativity  were small but significant (r =0.15 to 0.22), indicating that they all are linked to the bigger concept of creativity.The demographic information of the BIG (population-based) study sample is displayed in Before performing the correlation analyses, the divergent thinking scores , convergent thinking scores (RAT), and creative achievements (CAQ) were normalized using rank-based transformation based on Blom's formula  in orderr =0.17 to 0.22, p < 0.012  or between ASD scores and either of the convergent or divergent creativity measures (p > 0.26).We found significant correlations in the BIG sample between the total number of ADHD symptoms in the population and all the variables of the divergent thinking task (AUT), We explored if there were associations between the symptom subscales on ADHD and ASD and convergent or divergent thinking. In r = −0.18, p = 0.01). Second, there was a nominal significant negative correlation between the subscale “problems with imagination” and originality of the AUT . The “problems with imagination” subscale includes items such as “I find making up stories easy” and “as a child, I enjoyed playing games involving pretending with other children”. Hence, according to these results, having more problems with imagination is associated with lower flexibility and originality. Third, a positive correlation between the subscale “social difficulties” and convergent thinking was found . This indicates that having less social skills/more social difficulties is associated with increased convergent thinking.Although we found no significant associations between the total number of ASD symptoms and convergent or divergent thinking scores, taking a closer look at the ASD subscales revealed three interesting links with creativity. First, there was a nominal significant negative correlation between the subscale “problems with imagination” and flexibility of the AUT . There were, however, two correlations that reached nominal significance: a positive link was seen between ASD symptoms and creative achievements in the science/interventions subscale (r = 0.10 p = 0.03), with a role for the symptom domain of attention to detail , possibly due to limited imagination skills  in the IMpACT2 study.To learn more about the relationship between ADHD symptoms and divergent thinking we combined the population-based sample (BIG) with the IMpACT2 sample, a case-control study  in explaining divergent thinking. This means that, inindividuals with a diagnosis, the number of ADHD symptoms does not explain variance in divergent thinking scores. No effects of current psychostimulant medication use were found on divergent thinking  which is in line with previous research . FurtherThe current study is the first to examine both ADHD and ASD symptoms and their relation to several measures of creativity in the same population sample. This allowed us to compare symptoms of ADHD and ASD on multiple aspects of creativity. In addition, the large population sample made it possible to investigate if distinct symptom profiles related to ADHD or ASD were associated with specific types of creativity. However, the current study also holds several limitations that should be taken into account. First, the data were collected as part of multiple waves of testing and therefore various measures were collected at different time points which may have influenced our results. Second, while it is commendable to be able to report on three different constructs of creativity  it is important to note that results can deviate based on the creativity domain that is tapped by different tests , 120. InTo conclude, the neurodevelopmental conditions and associated symptoms of ADHD and ASD are well known for the difficulties they cause in functioning in daily life as expected by modern society. Individuals with ADHD or ASD might experience difficulties in school, work, and in their relationships , 125. Duhttps://www.impactadhdgenomics.com/ and/or https://www.ru.nl/donders/research/research-facilities-projects/cognomics/.The datasets presented in this article are not readily available because conditions for data use apply. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by CMO Region Arnhem/Nijmegen, Netherlands. The patients/participants provided their written informed consent to participate in this study.PV, BJ, and MH collected the data. VT-P and MH performed the analysis. MB and MH coded the creativity data. MS, MB, EK, and MH designed the analysis. BF and MH were involved in designing and setting up the IMpACT and BIG studies. MS, VT-P, and MH wrote the paper with contributions from all the authors. All authors contributed to the article and approved the submitted version.MH was supported by a personal Veni grant from the Netherlands Organization for Scientific Research . BIG: This study used the BIG database, which was established in Nijmegen in 2007. This resource is now part of Cognomics, a joint initiative by researchers of the Donders Centre of Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience Departments of the Radboud University Medical Centre, and the Max Planck Institute for Psycholinguistics. The Cognomics Initiative was supported by the participating departments and centres and by external grants, including grants from the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL) and the Hersenstichting Nederland. In particular, the authors would also like to acknowledge grants supporting their work from the Netherlands Organization for Scientific Research (NWO), i.e. the NWO Brain & Cognition Excellence Program (grant 433-09- 229) and the Vici Innovation Program (grant 016–130-669 to BF). Additional support is received from the European Community's Seventh Framework Programme (FP7/2007 – 2013) under grant agreements n° 602805 (Aggressotype), n° 603016 (MATRICS), n° 602450 (IMAGEMEND), and n° 278948 (TACTICS), and from the European Community's Horizon 2020 Programme (H2020/2014 – 2020) under grant agreements n° 643051 (MiND) and n° 667302 (CoCA). IMpACT: We acknowledge funding from the Netherlands Organization for Scientific Research (NWO), the Vici Innovation Program (grant 016–130-669 to BF). The work was also supported by grant U54 EB020403 to the ENIGMA Consortium from the BD2K Initiative, a cross-NIH partnership, and by the European College of Neuropsychopharmacology (ECNP) Network “ADHD Across the Lifespan.”BF has received educational speaking fees from Medice. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Individuals with ADHD reported significantly more hypersexual behaviors than non-ADHD individuals, whereas no differences were found concerning risky sexual behaviors or sexual dysfunctions. In women with ADHD, hypersexual behaviors, sexual risk-taking as well as sexual dysfunctions were closely related to symptoms of emotional dysregulation, impulsivity, and oppositional symptoms. In men with ADHD, the associations between ADHD symptomatology and the sexuality-related measures were less clear, however, signs of emotional dysregulation seemed to be relevant as well. Since individuals with ADHD seem to be at an increased risk of some peculiarities in sexual behavior, sexuality-related issues should be routinely addressed during clinical consultations to provide more holistic treatment in order to enhance individual well-being and quality of life.Establishing a secure sexual identity is a major developmental goal of an individual's transition from childhood to adolescence and the years that follow. Attention deficit/hyperactivity disorder (ADHD) as a neurodevelopmental disorder defined by the core symptoms of inattention, hyperactivity, and impulsivity, but also with emotional dysregulation, oppositional behaviors, or disorganization appearing early in life, can affect several areas of an individual's personal and social development, including sexual health. Yet, the scientific knowledge about the relationship between ADHD and sexual functioning is still scarce. Using an anonymous online survey, we compared different sexual behaviors including risky sexual behaviors, hypersexual behaviors, and sexual dysfunctions between 206 individuals with ( Establishing a secure sexual identity is a major developmental goal of an individual's transition from childhood to adolescence and in the years that follow. During puberty, not only do physiological and anatomical changes occur, but adolescents also become aware of sexual arousal, desires, and functions, and they begin to develop self-oriented and interpersonal sexual behaviors . SeveralAttention deficit/hyperactivity disorder (ADHD) is a frequent developmental disorder appearing early in life. Meta-analyses have estimated the worldwide prevalence of ADHD to be 5.3% in children and adolescents and 2.5% in adults , 5, withAlthough behavioral characteristics of ADHD might also imply positive personal features that can support and sustain high functioning and flourishing life, such as cognitive dynamism, energy, divergent thinking, hyper-focus, non-conformism, adventurousness, self-acceptance and sublimation , diagnosADHD is further associated with significant impairments in interpersonal relations in the family and peer context . Less stStudies on the impact of ADHD on sexual development are yet scarce. In a 3-year follow-up study, no statistically significant differences in Tanner stages of sexual development were found between children aged 10 and 14 years with and without ADHD . MoreoveConcerning risk-taking behavior in the sexual domain, two studies have found a younger mean age of first sexual intercourse in young adults with ADHD compared to individuals without ADHD , 27. FloA higher number of sexual partners among individuals with ADHD was found in several studies , 26. YouEmerging research in the past decade also highlights a high rate of co-occurring ADHD in hypersexual individuals . Almost Another study in an ADHD outpatient sample  found prThe present study aimed to further elucidate the relation between ADHD and different aspects of sexual behavior and functioning. Given the limited number of studies and partly conflicting previous results, the present study followed an exploratory approach and thus no specific hypotheses were formulated. Specifically, we investigated risky sexual and hypersexual behaviors as well as sexual dysfunctions in women and men with ADHD in comparison to non-ADHD women and men.Data were collected in 2021 between July and October by means of an online survey, conducted with SoSci Survey software . The onlThe clinical group consisted of an outpatient sample, who had been diagnosed by a team of specialized professionals including psychiatrists, psychologists and nurses and underwent an extensive diagnosing process consisting of questionnaires, interviews and neuropsychological tests at the department of psychiatry and psychotherapy of the University Medical Center of the Johannes Gutenberg University Mainz in Germany. Moreover, ADHD participants were recruited via ADHD specific Internet fora. Non-ADHD participants were recruited online as well by displaying the study call on different social media platforms and by spreading the study call through mailing lists. All information was collected anonymously, and the subjects were informed that the participation was voluntary. All participants were informed that the present study aimed at assessing sexual behaviors before study participation. Before participants were able to answer the online questionnaire they had to hit a button stating that they have read the study information and that they are willing to participate in the present study.N = 344 valid cases were recorded. Of the valid cases 38 already left the survey before answering the questions about a current ADHD diagnosis. Furthermore, we excluded all participants who did not complete the whole questionnaire. Thus, our final sample consisted of 206 participants of whom 139  were diagnosed with ADHD and 67  had not received an ADHD diagnosis. Altogether we excluded 76 ADHD patients (35.3%) and 24 non-ADHD (26.4%) participants. The exclusion rate did not differ between ADHD and non-ADHD participants . Furthermore, those ADHD participants who were excluded because they did not complete the whole questionnaire  did not have a significantly higher ADHD symptom load measured with the SR-WRAADDS than those ADHD individuals who completed the whole questionnaire . Thus, it is unlikely that non-completion of the study varied systematically depending on the ADHD symptom severity.In total, the survey was clicked 921 times and a total number of Since the sample size of individuals who identified themselves as diverse was too small, we could not use this group in the gender-specific analyses. However, when analyzing the whole sample, individuals who described themselves as diverse were included.M = 36.8 years old , while the non-ADHD group was on average M = 34.3 years old . Distribution of biological sex  and age  did not differ significantly between the ADHD and non-ADHD participants. Of the included 139 ADHD patients 32 (23.0%) received their ADHD diagnosis at the outpatient center of the Department of Psychiatry and Psychotherapy of the University Medical Center Mainz. Of the ADHD individuals from the outpatient center 58.1% were women and they were on average 37.2 years old (SD = 10.3) and had a mean SR-WRAADDS sum score of 204.7 (SD = 30.7). In contrast, 66.7% of those ADHD individuals recruited online were women, they were on average 36.5 years old (SD = 10.4) and had a mean SR-WRAADDS sum score of 204.3 (SD = 33.9). Thus, age , gender  and ADHD symptom load  did not differ between ADHD patients from the outpatient center and those recruited online.The ADHD group was on average n = 24 (17.3%) answered that they were currently receiving no kind of treatment for their ADHD. Of those who were receiving any kind of treatment, n = 61 (53.0%) were currently treated psychotherapeutically, n = 88 (76.5%) were currently treated pharmacologically, n = 38 (27.3%) were receiving both psychotherapeutic and pharmacological treatment, and n = 15 (13.0%) patients were undergoing other sorts of treatment such as occupational therapy or neurofeedback. Since no further differentiation of the substances used in the pharmacological treatment was made, we did not consider this information for further statistical analyses.Regarding treatment in the ADHD group, Comparisons of the mean sum scores of both ADHD and non-ADHD groups on the SR-WRAADDS showed that individuals with ADHD had significantly higher scores on all subscales see . This acThe Self-Report Wender-Reimherr Adult Attention Deficit Disorder Scale  wasThe Sexual Risk Survey  is a quThe HBI-19  is a selThe German version of the Sexual Behavior Questionnaire SBQ-G, , 53, 58], 5853, 5T-tests. First, ADHD and HC  groups were compared regarding their sexual orientation and sexual experience by means of Chi 2-tests. Further, we compared differences in the mean frequency of risky sexual behavior in the two groups for the whole sample and separated by the gender binary system (women/men). Although we implemented the non-binary system in the survey, the sample sizes of the other categories were too small to be included in further statistical analyses. Correlations were further calculated between ADHD symptomatology measured with the SR-WRAADDS and sexual risk behavior measured with the SRS. Moreover, we compared differences in the mean frequency of hypersexual behaviors using the HBI-19 in the two groups within the whole sample, and separately for women and men using T-tests. We also calculated correlations between ADHD symptoms and hypersexual behavior using the SR-WRAADDS sum scores and the HBI-19 sum scores and its three factors . Additionally, we calculated a backward step binary logistic regression using the SR-WRAADDS subscale scores as predictors and the HBI-19 cut-off value as dependent variable, both in the whole sample and separately in women and men with ADHD, in order to examine the predictive power of the ADHD symptoms on hypersexual behaviors. Further, we analyzed the frequency of sexual dysfunctions in the ADHD and non-ADHD groups such as erectile dysfunction, delayed ejaculation, early ejaculation, and low orgasm satisfaction within men and low orgasm satisfaction, sexual pain, and failure to achieve orgasm within women using Chi 2-tests. Finally, we calculated correlations between ADHD symptoms using the SR-WRAADDS [WR-SR, . Furthermore, no differences were found concerning the number of ADHD and non-ADHD participants who reported that their first sexual experience was an experience of sexual abuse  reported about an experience of sexual abuse significantly more often than men with ADHD  , whereas this significant pattern was not found in individuals without ADHD .On average, individuals with ADHD were not significantly younger at the time of their first sexual experiences. However, when comparing women and men separately, a younger age was found in women with ADHD than in non-ADHD women, while no differences occurred when comparing male participants see . No signbuse see . HoweverNo significant differences were found concerning self-reported sexual orientation between individuals diagnosed with ADHD and those without ADHD see . ParticiIndividuals with ADHD had significantly higher HBI-19 total scores and significantly higher scores on the HBI-19 subscales  compared to individuals without ADHD. However, no significant difference was found in the number of participants in the two groups who were at or above the pre-defined HBI-19 cut-off value of 53, which allows to classify an individual as hypersexual see . When coT = −4.57; p < 0.001) and significantly higher scores in all subscales  than women with ADHD. Furthermore, significantly more men with ADHD were above the HBI-19 cut-off value than women with ADHD  and could thus be classified as hypersexual.Finally, it could be observed that men with ADHD had significantly higher HBI-19 total scores , the subscales temper , disorganization , oppositional symptoms , and social attitudes  on the one side and the HBI-19 sum score on the other side. The HBI-19 control subscale was significantly associated with the SR-WRAADDS sum score , the subscales temper , emotional over-reactivity , disorganization , oppositional symptoms , and social attitudes . The HBI-19 consequences subscale was also significantly associated with the SR-WRAADDS sum score , with the subscales disorganization , oppositional symptoms , and social attitudes . Finally, the HBI-19 coping subscale was significantly correlated with the SR-WRAADDS sum score  and with the subscale oppositional symptoms .To determine which of the SR-WRAADDS symptom scales were related to hypersexual behaviors, we calculated a correlation analysis between the subscales and sum scores of the SR-WRAADDS and the HBI-19 for the whole sample and separately for women and men with ADHD. Using the whole sample we found significant correlations between the SR-WRAADDS sum score , while oppositional symptoms  and social attitudes  were positive predictors of hypersexuality. The final regression model explained 18% of the variance of the HBI-19 cut-off value and 76.3% of all participants could be correctly classified as hypersexual or not. In women, only the impulsivity subscale score was a significant predictor , while all other variables were not included in the final regression model. The final regression model explained 16.2% of the variance of the HBI-19 cut-off value and 85.4% of the female ADHD individuals were correctly classified as being below or above the HBI-19 cut-off. In men, the subscale affective lability was negatively associated with the HBI-19 cut-off , while the social attitudes subscale was positively associated with the HBI cut-off . The final regression model explained 26.2% of the variance of the HBI-19 cut-off value and 63.6% of the male ADHD individuals were correctly classified as being below or above the HBI-19 cut-off.Furthermore, we calculated a backward step binary logistic regression with the SR-WRAADDS subscale scores as predictors and the HBI-19 cut-off as dependent variable separately for the whole sample and for women and men with ADHD. In the whole sample, hyperactivity was a negative predictor . All other variables did not differ significantly between men and women with ADHD.No group differences were found in the comparison of risky sexual behaviors using the SRS. However, men with ADHD reported more frequently about leaving a social event with a person they have just met than men without ADHD see . When coIn order to determine whether or not ADHD symptomatology was associated with sexual risk-taking behavior, we calculated a sexual risk score by summing up the raw values of the variables shown in In women, ADHD symptomatology in general was positively associated with sexual risk-taking behavior. Furthermore, a significant positive correlation was found between temper, impulsivity, and oppositional symptoms and sexual risk-taking. In men, only temper was significantly associated with sexual risk-taking, while all other scales did not show statistically significant associations.Men with ADHD did not report more or less frequently about erectile dysfunctions during masturbation or sexual intercourse, about problems with delayed or early ejaculation and were just as satisfied with their orgasm as men without ADHD see . In womeCorrelational analysis in ADHD participants showed only weak associations between sexual dysfunctions and ADHD symptoms. In women, only temper and affective lability showed a small but significant association with low orgasm satisfaction, while academic problems were positively related to the failure to reach an orgasm during masturbation or sexual intercourse and to sexual pain see . In men,The present study is among the first assessing a wide variety of self-reported sexual behaviors in a sample of adults with ADHD in comparison to non-ADHD adults from the general population. Furthermore, we evaluated the association between different facets of ADHD symptomatology and (problematic) sexual behaviors and analyzed differences between men and women with ADHD.In summary, we found no differences regarding risky sexual behaviors and sexual dysfunctions in the comparisons between the ADHD and the non-ADHD groups. Nevertheless, participants with ADHD reported significantly more hypersexual behaviors in a sub-clinical level, including higher HBI-19 total scores and higher scores on the HBI-19 subscales coping, consequences and control than participants without an ADHD. In the comparisons separated by gender, both women and men with ADHD showed significant higher HBI-19 sum scores and significant higher scores on its subscale control. However, we found no significant difference in the number of participants in the ADHD and non-ADHD groups, who were at or above the pre-defined HBI-19 cut-off value of 53 for the classification of an individual as hypersexual.Usually going along with a higher number of sexual partners, there are other risky sexual behaviors in adults with ADHD. ADHD individuals usually show an earlier initiation of sexual activity and sexual intercourse, have more partner pregnancies during adolescence, use condoms during sexual intercourse less often, are more frequently diagnosed with a sexually transmitted infection, and use alcohol and drugs during sexual contacts more frequently compared to adults without ADHD , 32, 34.In samples from the general population but also in clinical samples, a relation between a higher impulsivity and more risky sexual behaviors was repeatedly found –63. In tIn both men and women with ADHD, the temper subscale was also positively correlated with risky sexual behaviors. On the one side, frequent emotional outbursts also show a close relation to oppositional or conduct problems  and coulWhile some studies have found a considerable prevalence of ADHD in samples of individuals reporting about hypersexual behaviors , 76–78, In both men and women with ADHD hypersexual behaviors were also related to the SR-WRAADDS subscale social attitudes. This subscale includes items like “difficult, strained relationship with life partner”, “problems making friends and maintaining friendships, “few social contacts.”, or “cool relationships with life partners”. It could be hypothesized that individuals scoring high on this subscale view sexuality in general and sexual relationships in specific rather unemotional and as a mere satisfaction of their own needs without caring much about the feelings and needs of the sexual partner. This would also explain why the HBI-19 subscale coping was the only one that was actually not related to the social attitudes subscale, underscoring that in these individuals' hypersexual behaviors cannot be seen as a means of dysfunctional emotion regulation. Moreover, it is known that fear of intimacy is increased in ADHD patients and correlates with the number of ADHD symptoms as well as with biographical experiences of devaluation and rejection and with risky sexual behavior, particularly among the inattentive subtype of ADHD, pointing that the inability for mutual dialogue, attachment and support could be linked to risky and hypersexual behaviors as well .Although previous studies suggested that women as well as men with ADHD report more frequently about sexual dysfunctions compared to non-affected individuals from the general population , 44, no p = 0.08). Based on previous and our findings, it could also be possible that due to a lower overall satisfaction within sexual and romantic relationships (Moreover, we did not find any differences in self-reported sexual orientation between individuals with and without ADHD. Corresponding to large epidemiological studies, in both groups a heterosexual orientation was reported most frequently, followed by a bisexual orientation, and a homosexual orientation . Howeverionships , 91, ADHBecause information gathered for the present study were based on self-report only and the chosen approach was rather exploratory, the results are limited and should be interpreted cautiously. Further, other limitations should be addressed: We did not calculate the sample size a priori and our final sample was quite small, thus generalizability of the results is limited. Especially the sample of non-ADHD participants was quite small. We could only include 21 men without ADHD, which could have hampered the detection of gender specific group differences Further, although all ADHD participants have specified that they were diagnosed by a psychologist or psychiatrist, one cannot be sure that this was actually the case. However, the ADHD individuals had significantly higher SR-WRAADDS total scores and scored significantly higher on every subscale, underscoring that they showed a more pronounced ADHD symptomatology than the non-ADHD individuals. Another important limitation of the present study is related again to possible sampling biases: given we recruited participants from the general population using ADHD specific Internet fora and other online channels, namely different social media platforms and mailing lists, it might have contributed to a selection of highly motivated individuals in the clinical and control group. Although we excluded cases that did not complete the whole questionnaire, the intensity of ADHD symptomatology did not differ between those ADHD participants who completed the whole questionnaire and those who did not. Furthermore, our results could also be limited by the fact that especially participants with a higher interest in sexuality-related issues or participants with per se more sexual problems were more likely to participate in the present study, because our study call included the information, that the online survey would assess sexual behaviors and sexual problems. This could have led to an overestimation of hypersexual behaviors and sexual dysfunctions. Such sampling biases can affect the internal validity of an analysis by leading to inaccurate estimations of relationships between variables and the external validity of an analysis, thus the results from a biased sample may not generalize to the population. Furthermore, although we assessed how many individuals were currently treated with medication, we did not assess the kind of medication our ADHD individuals were treated with. Since previous research has shown that especially stimulants could have an influence on sexual functioning, the specific medication should be considered in future studies assessing sexuality related issues in patients with ADHD , 92, 93.Future studies should assess the perception concerning sexuality-related issues of the intimate partners of patients with ADHD. To fulfill this purpose, future studies could for example use an interview design assessing sexual experiences of both the patients and their partners. Due to a higher likelihood of risky sexual behaviors in patients with ADHD, they might also be at an increased risk of sexual victimization, a highly relevant issue that has so far been mainly neglected by previous research. Finally, as symptoms of emotion regulation seem to be especially relevant concerning the occurrence of sexual problems in patients with ADHD, future studies should focus more strongly on this relationship.A healthy sexuality is of utmost importance for overall well-being . HoweverThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Psychological Chamber of the University Medical Center Hamburg-Eppendorf, Germany. The patients/participants provided their written informed consent to participate in this study.PGH, DT, DS, SB, and WR: conceptualization and methodology. PGH, DT, and WR: formal analysis. PGH, DT, and LB: investigation. WR: resources. PGH, DT, and LB: data curation. PGH, DT, and WR: writing—original draft preparation. PGH, WR, DT, SB, and PR-J: writing—review and editing. PGH, DT, DS, LB, PR-J, and WR: visualization. WR: administration. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


H domain, F6, which we generated by sequentially panning large phage-displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized VH domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants.The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human V  •H with broad neutralization against SARS-CoV-2 VOCsIdentification of a human V•CryoEM reveals a unique binding paratope of F6 involving the framework region•The biparatopic antibody (F6-ab8-Fc) enhances the neutralization potency•F6-ab8-Fc reduces disease burden and protects mice from the Beta variant mortality Immunology; Virology. To treat infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, various therapeutics have been explored, such as convalescent patient sera (Since the start of the coronavirus disease 2019 (COVID-19) pandemic , more thent sera , neutralent sera , and smaent sera . The spient sera , is a maent sera .The receptor binding domain (RBD) within the subunit 1 (S1) region of the spike protein exhibits a high degree of mutational plasticity and is prone to accumulate mutations that lead to partial or full immune escape . The WHOH domain (VH F6) that shows broad neutralizing activity against SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, and Omicron BA.1 and BA.2 VOCs. VH F6 binds a relatively conserved portion of the receptor binding motif (RBM), using a unique framework region (FR)-driven paratope. By combining VH F6 with our previously identified Ab, VH ab8, we developed a biparatopic Ab (F6-ab8-Fc), which exhibits potent neutralizing activity against all tested SARS-CoV-2 variants including the Omicron BA.1 and BA.2 VOCs. Prophylactic dosing with F6-ab8-Fc reduced viral titers in the lungs of a mouse model and high therapeutic doses of F6-ab8-Fc protected against mortality. Our study identifies a novel broadly neutralizing VH domain Ab with a unique paratope and provides a potent biparatopic Ab (F6-ab8-Fc) against all tested SARS-CoV-2 variants, including the presently dominant Omicron BA.1 and BA.2 sub-lineages.In this study, we identify a VH domains against SARS-CoV-2 VOCs, we adopted a sequential panning strategy to pan our in-house large VH phage library. We used RBD containing the E484K mutation for the first round of panning, wild-type (WT) RBD for the second, and the spike protein S1 domain-containing K417N, E484K, and N501Y mutations for the third  of 5.1 and 7.2 nM, respectively , Alpha, Beta, Gamma, and Delta spike pseudotyped viruses with a 50% inhibition concentration (IC50) of 31.08, 40.32, 3.62, 6.23, and 0.86 nM, respectively  obtained by BLItz  structure of VH F6 bound to a prefusion stabilized Beta spike trimer at a global resolution of 2.8 Å  of F6—a heavy-chain (VH) only Ab—expands the interaction interface beyond the conventional complementarity-determining regions (CDRs)  D. SpecifRBD peak D. In addRBD peak C–S3E. Owd to ab8   polypeptide linker with the C terminal fused to the human IgG1 fragment crystallizable region (Fc)  A. Additiion (Fc) . The bipion (Fc) A. Additiion (Fc) B–S6F. F6ion (Fc) B–3D. Impectively D. The hiH F6 (H F6 and F6-ab8-Fc against Omicron BA.1. These constructs include F6-F6 (two VH F6 connected by a tandem polypeptide linker 5×(GGGGS), F6-Fc (an F6 fusion with an Fc using the same linker as that in F6-ab8-Fc), F6-F6-Fc . F6-F6 neutralized with higher potency than F6, and F6-F6-Fc had the highest potency against BA.1 , while evading neutralizing Abs . The RBDH) Ab, F6 that can broadly neutralize Alpha, Beta, Gamma, Delta, and Omicron variants. VH F6 targets a class-4 epitope that spans the RBD peak and valley outer-face, and partially overlaps with the hACE2 binding interface. Importantly, the CryoEM structure of VH F6 in complex with the Beta spike protein revealed that VOC mutations lie either outside of the VH F6 epitope  or within its periphery . The VH F6 epitope bears a high degree of similarity to the full-length Ab A19-46.1, which can also neutralize the Omicron BA.1 variant  compared to other VOCs. The reasons for these differences in neutralization potency are unclear but could be related to the different spike mutations in VOCs which may influence spike conformation/processing on the virion surface. Interestingly, VH F6 exhibits a higher neutralization potency for Omicron sub-lineage BA.2 than BA.1. The increased potency relative to BA.1 may be explained by the unique BA.1 mutation (G446S) within the F6 footprint that could disrupt F6-BA.1 binding.Voviruses B and 3D,al spike D. The inH F6 primarily belongs to the class 4 Ab group, which also contains the highly potent and patient-derived Abs C002   B, which on BA.1) C. Howevein vivo  with a unique paratope and epitope, and which neutralized all SARS-CoV-2 variants tested. The F6 epitope may be targeted to elicit broadly neutralizing Abs and vaccines against circulating SARS-CoV-2 variants. The biparatopic bispecific Ab, F6-ab8-Fc, with its broad neutralization activity and in vivo activity presents a new Ab therapeutics against current SARS-CoV-2 VOCs.In summary, we have identified a broadly neutralizing antibody domain  activity, and binding to CD16A may help to mobilize ADCC killing infected cells. However, Fc receptor binding may also have the potential to contribute to the immunopathology of SARS-CoV-2 (via antibody-dependent enhancement). The detailed role of Fc effector function for F6-ab8-Fc in the protection of mice from lethal SARS-CoV-2 challenge needs to be further investigated by future studies. Moreover, it is possible that future VOCs may evade F6-ab8-Fc, and thus screening and testing of this molecule should continue as new VOCs emerge. On ab8-resistant variant Omicron BA.1, the higher neutralization potency of F6-F6-Fc than F6-ab8-Fc highlights the more important role of avidity compared to biparatopicity. It remains to be seen whether F6-F6-Fc outperforms F6-ab8-Fc (thus monoparatopic avidity outweighs biparatopicity) on other SARS-CoV-2 VOCs such as Alpha and Delta.LIWEI171@pitt.edu).Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Wei Li  and 293T (ATCC) were cultured at 37°C in Dulbecco’s Modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 10 mM HEPES pH 7.3, 1 mM sodium pyruvate, and 100 U/mL of penicillin–streptomycin. 293T was cultured in DMEM medium. 293T-Spike and 293T-ACE2 were cultured in DMEM medium containing 100 μg/mL Zeocin. Expi293F was maintained in Expi293™ Expression Medium . The SARS-CoV-2 spike pseudotyped HIV-1 backboned virus were packaged in 293T cells after transfecting pNL4-3.luc.RE and pcDNA3.1-spike plasmids . The SARS-CoV-2 live virus variants  ordered from BEI Resources and propagated VeroE6 cells. The mouse ACE2 adapted SAR-CoV-2 virus (Beta variants) gene recovered by the reverse genetics was produced in VeroE6 cells. All work with infectious SARS-CoV-2 was performed in Institutional Biosafety Committee approved BSL3 facilities using appropriate positive pressure air respirators and protective equipment.The recombinant proteins RBD mutants  and RBD-Fc were subcloned into pcDNA3.1 or pIW-Zeo expression plasmids, and expressed in Expi293F cells. Proteins with his tag were purified by Ni-NTA affinity chromatography and protein with Fc tag purified by protein A chromatography. Protein purity was estimated as >95% by SDS-PAGE and protein concentration was measured spectrophotometrically .H F6 antibody was identified by panning of the phage library. VH ab8 was previously identified by our lab. F6-F6, F6-Fc, F6-ab8-Fc, F6-F6-Fc were cloned into pIW-Zeo expression plasmids, and expressed in Expi293F cells. MERS-CoV-specific IgG1 m336 sequences cloned into the pDR12 plasmid and expressed in Expi293F cells. VH ab8 and VH F6 (in a phagemid pComb3x with a Flag tag) was expressed in HB2151 E. coli. Antibodies with his tag were purified by Ni-NTA affinity chromatography and antibodies with Fc tag purified by protein A chromatography.V5 PFU of mouse-adapted SARS-CoV-2 Beta variant. For evaluating prophylactic efficacy of F6-ab8-Fc, mice were intraperitoneally treated (12 h before infection) with 800 μg or 50 μg of F6-ab8-Fc followed by intranasal challenge with 105 PFU of mouse-adapted SARS-CoV-2 Beta variant. For evaluating the therapeutic efficacy of F6-ab8-Fc, mice were intraperitoneal injection with 800 μg or 50 μg of F6-ab8-Fc 12 h following infection. Four days post infection, mice were sacrificed and perfused with 10 mL PBS. Then lung was harvested for viral titer as determined by the plaque assay.For the mouse model, BALB/c mice purchased from Envigo  were used for all experiments. They are drug/test naïve and negative for pathogens. Animals were not involved in any previous studies. Animals were housed in groups of 5 animals per cage and fed standard chow diet. The study was carried out in accordance with the recommendations for care and use of animals by the Office of Laboratory Animal Welfare (OLAW), National Institutes of Health and the Institutional Animal Care. All mouse studies were performed at the University of North Carolina  using protocols (19-168) approved by the UNC Institutional Animal Care and Use Committee (IACUC) and all virus studies were performed in ABSL3 facilities at UNC. Virus inoculations were performed under anesthesia and all efforts were made to minimize animal suffering. For evaluating prophylactic efficacy of F6-ab8-Fc, mice were intraperitoneally treated (12 h before infection) with different doses of F6-ab8-Fc followed by intranasal challenge with 10The SARS-CoV-2 RBD, S1 and S trimer mutants were ordered from Sino Biological (USA). The VH F6 and VH ab8 were expression in HB2151 bacteria cells as previously described . F6-F6, Ninety-six-well ELISA plates (Corning 3690) were coated with the RBD, S1 mutants or S trimer variants at a concentration of 5 μg /mL (diluted with 1xPBS) and incubated at 4°C overnight (50 μL per well). The next day, plates were blocked with 150 μL 5% milk (Bio-Rad) in DPBS solution at room temperature for 2 h. Primary antibodies were diluted with the same 5% milk blocking buffer and 1:10 or 1:3 serial dilution series were conducted, with 1 μM as the highest concentration. After 2 h of blocking, the primary antibodies were added (50 μL per well) and incubated at room temperature for 2 h. After 2 h incubation, the plates were washed 4 times with 0.05% Tween 1xPBS (PBST) solution using a plate washer (BioTek). Secondary antibodies (anti-Flag-HRP or anti-Human Fc-HRP) were prepared with the same 5% milk at a dilution of 1:1000. 50 μL of secondary antibody was added into each well and incubated at room temperature for 1 h. To test F6-ab8-Fc binding to human FcγRs, F6-ab8-Fc was coated on plates followed by addition of the recombinant human FcγR protein in gradient concentrations. After washing, the binding was detected by HRP conjugated anti-His tag Ab. For testing binding of VH F6 and F6-ab8-Fc to Omicron BA.1 and BA.2 RBD and spike proteins, the RBD or spike were coated, and binding were detected by using HRP anti-FLAG tag for VH F6 and the HRP anti-human Fc Ab for F6-ab8-Fc. After 1 h incubation, the plates were washed 5 times with PBST. Fifty μL of TMB substrate (Sigma) was added into each well, allowed 1-2 min to develop color, then stopped with 50 μL H2SO4  and the plate scanned at 450 nm absorbance. The ELISA results were analyzed using GraphPad Prism 9.0.2.Antibody affinities were measured by biolayer interferometry BLItz . For VH F6 affinity determination, VH F6 was biotinylated with BirA biotin-protein ligase standard reaction kit . Streptavidin biosensors (ForteBio: 18–5019) were used for biotinylated VH F6 immobilization. For F6-ab8-Fc affinity determination, Protein A biosensors (ForteBio: 18-5010) were used for immobilization. Dulbecco’s phosphate-buffered saline (DPBS) (pH = 7.4) was used for baseline and dissociation collection. The detection conditions used were: (I) baseline 30s; (II) loading 120 s; (III) baseline 30 s; (IV) association 120 s with a series of concentrations ; (V) dissociation 240 s. The Ka and Kd rates were measured by BLItz software and KD was calculated for each antibody by the Kd /Ka ratio. For VH F6 - VH ab8 competition, Protein A biosensors (ForteBio: 18-5010) were used for RBD-Fc immobilization. The detection conditions used were (I) baseline 30s; (II) loading 120 s; (III) baseline 30 s; (IV) association 120 s with VH ab8; (V) association 120 s with VH F6.For cryo-EM, SARS-CoV-2 S trimer Beta mutant were deposited on grids at a final concentration of 2 mg/mL. Complexes were prepared by incubating S trimer Beta mutant with VH F6 at a molar ratio of 1:10. Grids were cleaned with H2/O2 gas mixture for 15 s in PELCO easiGlow glow discharge unit (Ted Pella) and 1.8 μL of protein suspension was applied to the surface of the grid. Using a Vitrobot Mark IV (Thermo Fisher Scientific), the sample was applied to either Quantifoil Holey Carbon R1.2/1.3 copper 300 mesh grids or UltrAuFoil Holey Gold 300 mesh grids at a chamber temperature of 10°C with a relative humidity level of 100%, and then vitrified in liquid ethane after blotting for 12 s with a blot force of −10. All cryo-EM grids were screened using a 200-kV Glacios (Thermo Fisher Scientific) TEM equipped with a Falcon4 direct electron detector and data were collection on a 300-kV Titan Krios G4 (Thermo Fisher Scientific) TEM equipped with a Falcon4 direct electron detector in electron event registration (EER) mode. Movies were collected at 155,000× magnification  over a defocus range of −3 μm to −0.5 μm with a total dose of 40 e – /Å2 using EPU automated acquisition software (Thermo Fisher).A detailed workflow for the data processing is summarized in 7MJI) or from homology modeling (VH F6)   were doc (VH F6) . Then, m (VH F6) , followe (VH F6) . Model v (VH F6) . Figures (VH F6) , and PyMWe constructed a structural model for the Omicron RBD complexed with F6 using the cryo-EM structure of F6/Beta RBD complex as template, and constructed the system for molecular dynamics simulations of this complex using the CHARMM-GUI Solution Builder module . The resSARS-CoV-2 spike Wuhan-Hu-1 (+D614G), Alpha, Beta, Gamma, Delta, and Omicron protein genes were synthesized and inserted into pcDNA3.1 . HEK293T cells  were used to produce pseudotyped retroviral particles as described previously . 60 h po5 cells) were seeded in 24-well tissue culture plates per well. Antibodies (VH F6 and F6-ab8-Fc) were serially diluted by two-fold with a starting concentration ranging from 4 μg/mL to 40 μg/mL (depending on the antibody being tested) and mixed with equal volume of 30-50 plaque forming units (pfu) of SARS-CoV-2. The following SARS-CoV-2 variants were used: isolate USA-WA1/2020 ; isolate hCoV-19/South Africa/KRISP-EC-K005321/2020 ; Alpha isolate USA/CA_CDC_5574/2020 ; Delta isolate hCoV-19/USA/PHC658/2021 ; Omicron BA.1 isolate hCoV-19/USA/MD-HP20874/2021 . The antibody-virus mixture was then incubated at 37°C in a 5% CO2 incubator for 1 h before adding to the Vero E6 cell seeded monolayers. The experiments were performed in duplicate. Following 1 h incubation at 37°C, an overlay media containing 1% agarose  was added into the monolayers. The plates were then incubated for 48–72 h and then cells were fixed with formaldehyde for 2 h. Following fixation, agar plugs were removed, and cells were stained with crystal violet. To precisely titrate the input virus, a viral back-titration was performed using culture medium as a replacement for the antibodies. To estimate the neutralizing capability of each antibody, IC50 was calculated by non-linear regression using the sigmoidal dose response equation in GraphPad Prism 9. All assays were performed in the University of Pittsburgh Regional Biocontainment Laboratory BSL-3 facility.Neutralization assays were performed using Vero E6 cells (ATCC CRL-1586). One day before the assay, the Vero E6 cells  of mouse-adapted SARS-CoV-2 B.1.351 MA10. For evaluating the therapeutic efficacy of F6-ab8-Fc, mice were intraperitoneal injection with 800 μg of or 50 μg of F6-ab8-Fc12 h following infection. 4 days after virus infection, mice were sacrificed, and lungs were harvested for viral titer by plaque assays. The caudal lobe of the right lung was homogenized in PBS. The homogenate was 10-fold serial-diluted and inoculated with confluent monolayers of Vero E6 cells at 37°C, 5% CO2 for 1 h. After incubation, 1 mL of a viscous overlay (1:1 2X DMEM and 1.2% methylcellulose) is added into each well. Plates are incubated for 4 days at 37°C, 5% CO2. Then, the plates are fixation, staining, washing and dried. Plaques of each plate are counted to determined virus titer. The study was carried out in accordance with the recommendations for care and use of animals by the Office of Laboratory Animal Welfare (OLAW), National Institutes of Health and the Institutional Animal Care. All mouse studies were performed at the University of North Carolina  using protocols (19-168) approved by the UNC Institutional Animal Care and Use Committee (IACUC) and all mouse studies were performed in a BSL3 facility at UNC.Eleven to twelve-month old female immunocompetent BALB/c mice  were used for SARS-CoV-2 eviously , 2021b EH F6 mediated inhibition of cell-to-cell fusion in the β-gal reporter assay, experiments were performed in triplicate. The paired Student t test was used to evaluate statistical differences. ∗p < 0.05, ∗∗p < 0.01. For the mouse model, the statistical significance of difference between F6-ab8-Fc treated and control mice lung virus titers was determined by the two-tailed, unpaired, student t test calculated using GraphPad Prism 9.0. A p value < 0.05 was considered significant. ns: p > 0.05, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.For ELISA, all the experiments were performed in duplicate and error bars denote ± SD, n = 2. For pseudovirus neutralization, all experiments were repeated at least twice in triplicate and error bars denote mean ± 1 SD, n = 3. For live virus neutralization, all experiments were repeated at least twice in triplicate and error bars denote mean ± 1 SD, n = 3. For the comparisons of F6-ab8-Fc and V