Rye from a single hybrid (KWS Bono) with an ergot alkaloid concentration of 392 ppb was processed with a roller mill to a processing index (PI) of 78.8 ± 2.29. Four treatments were used in a completely randomized design , where DRC (PI = 86.9 ± 4.19) was replaced by varying proportions of Rye . Liver abscess scores and carcass characteristics were collected at the abattoir. Carcass-adjusted performance was calculated from hot carcass weight (HCW)/0.625. Performance-adjusted NE was calculated using carcass-adjusted average daily gain (ADG), DM intake (DMI), and mean equivalent shrunk BW with the comparative NE values for rye calculated using the replacement technique. Data were analyzed using the GLIMMIX procedure of SAS 9.4  with pen as the experimental unit. Treatment effects were tested using linear and quadratic contrasts, as well as between diets with and without Rye. Replacing DRC with Rye linearly decreased (P ≤ 0.01) carcass-adjusted final BW, ADG, DMI, and gain:feed (G:F). Feeding rye linearly decreased HCW and longissimus muscle area (P ≤ 0.04). Distributions of liver scores and USDA grades for quality and yield were unaffected by treatment (P ≥ 0.09). Estimated replacement NE for maintenance (NEm) and gain (NEg) values for rye, when included at 60% of diet DM, were 1.90 and 1.25 Mcal/kg, respectively. Rye can be a suitable feed ingredient in finishing diets for feedlot steers. Estimated replacement values of Rye when fed at 60% of diet DM closely agreed with current tabular standards but, when included at 20% of diet DM, estimated NEm and NEg values of Rye were increased 9.5% and 12.8%, respectively. Net energy value of Rye for gain is approximately 84% compared to DRC; thus, the complete replacement of DRC with Rye depressed DMI, ADG, G:F, and carcass weight.Crossbred beef steers with a high percentage of Angus ancestry [ Increasing crop-rotation diversity offers a number of benefits to an integrated crops–livestock production system, including greater yield resiliency and enhanced yield increases compared to a monoculture or two-crop rotation . DiversiCereal rye offers several attributes that warrant consideration for inclusion as a component of an integrated crops–livestock system. Rye can be grazed, harvested for forage, or allowed to reach maturity for the harvest of grain and straw. Furthermore, rye is harvested earlier than row crops, allowing for greater manure application flexibility or planting of short-season forage crops if conditions allow. Newer hybrid rye (Rye) germplasms are particularly promising because of their enhanced yield potential and decreased ergot incidence compared to traditional open-pollinated rye cultivars .Multiple potential uses enhance the utility and acceptance of any crop by providing additional options and lessening the reliance on any one market channel. Cereal rye grain has not been traditionally thought of as a suitable cereal grain for finishing cattle. It has been recommended to only feed cereal rye to finishing cattle in limited amounts because of the negative effects of ergot ingestion and observed decreases in dry matter intake DMI; . Those rThe objectives of this experiment were to determine the effects of Rye inclusion on DMI, growth performance, and feed efficiency in finishing beef steers and to estimate net energy (NE) value. Our hypothesis was that cereal rye could be substituted for dry-rolled corn (DRC) in finishing beef diets and that increased inclusion rates would decrease growth performance and feed efficiency with no negative effects on carcass characteristics or the severity and incidence of liver abscesses.All procedures involving the use of animals in this experiment were approved by the South Dakota State University Institutional Animal Care and Use Committee . The experiment was conducted at the South Dakota State University Southeast Research Farm (SERF) located near Beresford, SD.Four treatments were used in a completely randomized design to evaluate animal performance and carcass traits and to estimate the NE value for Rye. Hybrid rye was substituted for DRC as follows: a basal finishing diet formulated [dry matter (DM) basis] with 60% corn grain  and three additional diets formulated with increasing proportions of Rye . All rye grain used was from the same hybrid  and from a single source. Each truckload of Rye was sampled on arrival at SERF and composited for ergot alkaloid analysis. Total ergot alkaloid concentration from the composited sample was 392 ppb on a DM basis .n = 240, initial shrunk body weight (BW), 404 ± 18.5 kg] were used in this experiment. Steers were sourced from a single consignment at one South Dakota auction facility and delivered to SERF. Steers were fed in 24 dirt-surfaced pens, resulting in six replications per treatment and 60 steers per treatment (n = 10 steers/pen). The dirt-surfaced pens had a 6.1-m concrete bunk apron, a continuous flow waterer on the fence line located 0.6 m from the bunk apron, and provided 54.4 m2 of pen space per steer and 61 cm of linear bunk space per steer. Cattle were processed on September 6, 2019, where BW was collected to be used for allotment purposes, a unique identification tag was applied to each steer, vaccines were administered against respiratory pathogens: infectious bovine rhinotracheitis, bovine viral diarrhea types 1 and 2, parainfluenza-3 virus, and bovine respiratory syncytial virus  and clostridial species , and administered pour-on moxidectin . The experiment was initiated on September 10, 2019 with a 19-d adaptation period and a 98-d finishing period, resulting in a total experiment length of 117 d. On September 30, 2019 (day 19), steers were administered a steroidal implant .Crossbred beef steers with a high percentage of Angus ancestry BW), kg; ] for theg; , respectively. The same was done for NEg, assuming DRC had an NEg value  of 1.49  with pen as the experimental unit. The model included the fixed effect of dietary treatment. Least squares means were generated using the LSMEANS statement of SAS and treatment effects were evaluated using orthogonal polynomials . Dry matP = 0.01; P = 0.03) and a tendency for increased ADG and G:F (P ≤ 0.07). Increased Rye linearly decreased ADG (P = 0.01) and quadratically decreased BW (P ≤ 0.04) from day 48 to day 117. Dry matter intake decreased quadratically (P = 0.03) from day 48 to day 75 with reduced DMI for 0:60 compared to treatments with lesser inclusion of Rye. Dry matter intake linearly decreased (P = 0.01) with increasing Rye inclusion from day 76 to day 117. Feed efficiency was linearly decreased by increased Rye (P = 0.05) from day 48 to day 75 but unaffected by treatment from day 76 to trial termination.Rye improved performance with linear increases in BW, ADG, DMI, and gain:feed (G:F)  between DRC:Rye and days on feed, where DMI did not differ between treatments initially but diverged during the experiment, resulting in decreased DMI with increased Rye inclusion . Comparative NEm and NEg values for Rye at 20%, 40%, and 60% inclusion levels were 2.08 and 1.41, 1.93 and 1.28, and 1.90 and 1.25 Mcal/kg for maintenance and gain, respectively.Using carcass-adjusted cumulative performance, Rye inclusion linearly decreased carcass-adjusted final BW, ADG, and G:F . Rib fat, kidney, pelvic, and heart fat (KPH) percentage, YG, RY, and estimated EBF percentage were unaffected by treatment (P ≥ 0.14). Dietary treatment tended (P = 0.07) to affect marbling quadratically with reduced marbling in the 0:60 treatment compared to treatments with lesser inclusions of Rye. Longissimus muscle area decreased with increased Rye inclusion (P = 0.04), as did AFBW (P = 0.01). Dietary treatment did not affect distributions of USDA YG or QG or severity or prevalence of liver abscess scores (P ≥ 0.09).Hot carcass weight linearly decreased with increased Rye  in the current experiment agree closely with previously published values for rye grain  did not affect the performance of growing Holstein calves  or finisNet energy dilution alone does not explain the increased ADG observed during the adaptation period and the lack of treatment effects on G:F from day 20 to day 47 in the current experiment. Negative effects of increased Rye inclusion on DMI, growth response, and feed efficiency were not apparent until after day 47. Taken together, these observations support the conclusions that exposure to increased amounts of ingested Rye or exposure over a prolonged period negatively affects growth and efficiency in finishing beef steers.Claviceps pupurea in ergot-infested grain; however, toxicosis and ergopeptide alkaloids are similar between the two sources . This agrees with experiments where steers fed endophyte-infested fescue seeds ate more slowly compared to their pair-fed counterparts on a negative control diet . DecreasThe degree of rye processing also may have contributed to decreased DMI. The PI for Rye chosen for this experiment was based upon suggested PI used for barley and wheat in finishing diets to minimize excess fines while enhancing ruminal starch degradability . ExcessiThe DPs for all treatments were less than expected in this experiment but consistent with the results observed by others during winter in the Midwest . The quaIndicators of carcass fatness  were unaffected by treatment. Longissimus muscle area and AFBW decreased with increased Rye inclusion, suggesting that Rye decreased muscling and frame size at increased inclusion rates. This result was unexpected and not easily explained. Greater substitution of rye grain for DRC decreased the dietary energy density. This, combined with the decreased DMI observed in the current experiment, should have resulted in less fat deposition with increased inclusions of Rye. An MP deficiency is consistent with decreased DMI and AFBW; however, MP supply was greater than the requirements in this experiment . Very liThese data indicate that Rye can be successfully fed to finishing beef steers. In this experiment, NEm and NEg values of Rye were 87.6% and 83.9% of the values for DRC, respectively, when completely replacing DRC. Blends of two-thirds DRC to one-third Rye supported increased carcass-adjusted growth performance and DMI compared to increased inclusions of Rye. Therefore, the combination of DRC and Rye could be a tool to optimize the NE content of Rye when fed to finishing cattle. Additional work is required to determine if the negative effects of increased rye inclusion on DMI and performance were caused by cereal rye per se, ergot alkaloid concentrations, or the degree of grain processing.


Certain personality traits and cognitive domains of executive functions (EF) are differentially related to attention deficit hyperactivity disorder (ADHD) symptoms in adolescents. This study aimed to analyze the five-factor model (FFM) personality characteristics in adolescents with ADHD, and to examine whether EF mediate the relationships between FFM personality traits and ADHD symptoms. A comprehensive diagnostic assessment, including ADHD clinical interviews, ADHD rating scales, neuropsychological EF testing  and a personality assessment was carried out in a sample of 118 adolescents , aged 12 to 16 years, and their parents and teachers. Adolescents with ADHD had lower scores than control participants on Conscientiousness and Agreeableness, and higher scores on Neuroticism. Structural equation models (SEM) showed that Conscientiousness directly influenced inattentive and hyperactive-impulsive symptoms, while Neuroticism, Agreeableness, and Extraversion directly affected hyperactive-impulsive symptoms. Only Conscientiousness exerted indirect effects on inattention, but not on hyperactivity-impulsivity symptoms, via EF; higher scores on Conscientiousness were related to higher scores on EF, which in turn were related to lower scores on inattentive symptoms. These findings corroborate the relationships between ADHD symptoms, FFM personality traits and EF and indicate the mediating effect of EF on the relationship between Conscientiousness and inattention. Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder characterized by a persistent pattern of inattentive and hyperactive/impulsive behaviors, leading to three presentations: inattentive (ADHD-IA), hyperactive/impulsive (ADHD-HI), and combined (ADHD-C) .ADHD symptoms reflect multiple causal pathways . In partIn children and adolescents with ADHD, several studies have shown links between top-down and bottom-up processes and ADHD symptoms ,14,15. IIn ADHD groups, EF has been traditionally evaluated with highly standardized and structured tasks that assess some top-down modulation, but not the affective or motivational component ,5. Thus,Personality traits are defined as the broad range of individual differences in emotion, cognition and behavior that show relative stability over time, have biological bases and are organized hierarchically ,31,32. CThe FFM groups personality traits into five broad domains: Conscientiousness, Neuroticism, Agreeableness, Extraversion and Openness, which are defined by more specific and narrow facets ,33. ConsConscientiousness involves constraining impulses, effortful attention, planful behavior, organization and achievement goal orientation. The overarching inhibitory component of Conscientiousness is associated with self-regulation, probably reflecting some kind of top-down regulation process ,42,43. TNeuroticism reflects the tendency towards excessive negative affectivity, emotional reactivity and distress, as well as low self-esteem. Agreeableness reflects compassion, empathy and cooperation whereas Extraversion reflects positive affect, assertiveness, activity level and sociability. Research to date suggests that some aspects of Neuroticism, Agreeableness and Extraversion  reflect bottom-up regulation processes ,17,40. MIn contrast to the four other personality traits, Openness, which refers to creativity, flexibility and willingness to explore new ideas and experiences, does not appear to be clearly linked to ADHD symptoms ,48. BaseThe research carried out to date has provided evidence supporting the hypothesized links between FFM personality traits, EF measures and ADHD symptoms ,16. MartTaken together, these findings suggest that EF, FFM personality traits and ADHD symptoms are interconnected in multiple ways. In fact, inattention  is associated with executive control and Conscientiousness, reflecting underlying top-down regulation processes, while hyperactivity-impulsivity  is linked to Agreeableness, Neuroticism and reactive control, reflecting underlying bottom-up regulation processes .Thus, these different patterns of associations between EF, FFM traits and ADHD symptoms may have two different causal pathways that mediate either more top-down executive influences or more bottom-up automatic influences. Consequently, individual differences in EF may reflect prefrontal top-down controlled influences, thus explaining the links between the FFM traits and ADHD symptoms in situations that demand more controlled than automatic responses. It is also crucial to consider that during adolescence, the neural systems  mediating top-down processes have not yet reached the level of that observed in adults . The incThe current study aimed to extend previous research on the relationship between EF, dispositional traits  and ADHD ,16,54 duM = 13.60, SD = 1.31, 68% males), while the control group consisted of 43 participants . Using the recommendations of McNeish  and for good fit . According to the observed distribution of ADHD using the whole distribution (not for each group), indirect effects and standard errors were estimated with the bootstrapping method  to obtain more accurate confidence intervals and, in this way, reduce the effects of the violation of the multivariate normal distribution of the observed variables involved in the model . However, there were significant age differences for Neuroticism  = 4.06, p = .001). A factorial ANOVA revealed that the group effect for age remained statistically significant  = 5.63, p = .005), with 14- and 15–year-old adolescents scoring significantly higher  than 12- and 13–year-old adolescents . The interaction effect between age and gender was not significant  = 0.21, p = .80). Additionally, there were significant gender differences for Extraversion  = 7.76, p = .01) and Agreeableness  = 8.17, p = .01). A factorial ANOVA showed that the group effect for gender did not remain statistically significant for Extraversion  = 2.78, p = .09) and Agreeableness  = 2.19, p = .14). The interaction effect between age and gender was not significant for both Extraversion  = 1.34, p = .26) and Agreeableness  = 1.21, p = .30).Full details of sample characteristics, measures of ADHD symptoms and cognitive EF can be found elsewhere , but thed = 0.78) and large effect sizes for IN (d = 1.24). In contrast, there were no significant differences between the ADHD and control groups for FL.Performance for each executive domain  for both the ADHD and control participants were documented in great detail elsewhere . Adolescd effect size and MANCOVA analysis for the two groups in personality traits are shown in Descriptive statistics, Cohen’s d = 0.47), medium for Agreeableness (d = 0.73) and very large for Conscientiousness (d = 1.66). MANCOVAs were performed to compare the FFM personality traits between the ADHD and control groups, with comorbidities included as covariates. MANCOVAs of Conscientiousness, Agreeableness and Neuroticism using Pillai’s trace revealed that after controlling for comorbidities, the group effects remained significant: V = .37, F = 21.99, p = .001, η2 = .37. Thus, the effect of comorbidities was not significant. There were no differences between the ADHD and control groups for Extraversion.Adolescents with ADHD showed significantly lower scores than control subjects on Conscientiousness and Agreeableness, and higher scores on Neuroticism . The effr(117) = .33, p < .001) and a high-to-moderate negative correlation with inattention (r(117) = —.60, p < .001) and hyperactivity-impulsivity (r(117) = —.37, p < .001). Neuroticism had a low negative correlation with WM (r(117) = —.21, p < .05) and IN (r(117) = —.19, p < .05), and a moderate positive correlation with inattention (r(117) = .30, p < .001) and hyperactivity-impulsivity (r(117) = .31, p < .001). Finally, Agreeableness only showed low and negative correlations with inattentive symptoms, r(117) = —.28, p < .001 and hyperactive-impulsive symptoms, r(117) = —.21, p < .001. No significant correlations were found between Extraversion and Agreeableness and EF. Inattentive and hyperactive-impulsive symptoms showed negative and low-to-moderate correlations with EF, ranging from r(117) = —.23, p < .01 (IN and hyperactive-impulsive symptoms) to r(117) = —.43, p < .001 (IN and inattentive symptoms).2 = 16.89, df = 12, p > .15; CFI = 0.98; TLI = 0.96; RMSEA = 0.05 (90% CI = 0.00–0.11) and SRMR = 0.03 , but not Neuroticism , Agreeableness  or Extraversion , had significant direct effects on inattention. The direct effects of Conscientiousness , Neuroticism , Agreeableness  and Extraversion  on hyperactive-impulsive symptoms were significant. Additionally, one indirect pathway of Conscientiousness on inattention via EF was significant . The indirect effects of Neuroticism , Agreeableness  and Extraversion  on inattention through EF were not statistically significant. Furthermore, no significant indirect effects of Conscientiousness , Neuroticism , Agreeableness  and Extraversion  on hyperactivity-impulsivity through EF were found. This model explained up to 58% of the variance for inattentive symptoms (R2 = 0.58) and 41% of the variance for hyperactive-impulsive symptoms (R2 = 0.41). Thus, EF mediate the association between Conscientiousness and inattention in adolescents. The final mediational models are shown in The results of the mediational models revealed that Conscientiousness  on inattention and hyperactivity-impulsivity via EF .Our data partially confirmed our first hypothesis, namely that the ADHD group would score lower on Conscientiousness and Agreeableness and higher on Extraversion and Neuroticism. We observed an association between ADHD and lower scores on Conscientiousness and Agreeableness and higher scores on Neuroticism. There was no significant correlation between ADHD and Extraversion. These findings are consistent with those of previous studies examining personality traits in children and adolescents with ADHD and reporting low Conscientiousness and Agreeableness and high Neuroticism ,16,35,37r = .33) and Neuroticism (r = -.19) and inhibition. Hoyle and Davisson [Importantly, we observed associations between ADHD and some of the personality traits closely related to self-regulation abilities that are considered impaired in this disorder ,47,85. FDavisson  suggesteDavisson ,47.Importantly, Extraversion did not appear to differ between the ADHD and control groups, as other studies with children and adolescents have found ,44. ThisIn summary, our findings suggest substantial links between lower Conscientiousness and Agreeableness and higher Neuroticism with ADHD symptoms. No differences were found between the ADHD and control groups in Extraversion, thus corroborating the suggestion of De Pauw and Mervielde  that somWith respect to our second hypothesis, namely that EF may mediate the relationship between Conscientiousness and inattention, our findings indicated the indirect effect of this personality trait on inattention via EF. Thus, as we had tentatively posited, mediation analysis revealed that EF explained the relationship between Conscientiousness and inattention in the whole sample of adolescents. Specifically, higher scores on Conscientiousness were related to higher scores on cognitive EF performances, which in turn were related to lower scores of inattentive symptoms. Similarly, Krieger et al.  found thAdditionally, individual differences in EF, involving top-down control mechanisms, could be associated with a breakdown in this pathway, explaining the relationship between Conscientiousness and only inattention, since all of them tap into self-regulation processes. Thus, when top-down processes become less available, EF become less efficient and the self-regulation processes, driven by mechanisms underlying Conscientiousness , are lesIn line with our hypotheses, there were no mediation effects between Neuroticism, Agreeableness and Extraversion and inattention and hyperactivity-impulsivity. Here, the mediation effects of EF were not considered since these FFM personality traits are linked more to bottom-up modulation (non-executive processes), as has been reported previously ,17. In fConsistent with our second hypothesis, our findings indicated that EF account significantly for the relationship between Conscientiousness and inattention and that, together with EF, they are the best predictors of inattention. Similar results were reported by Krieger et al.  who founOur results suggested that adolescents with ADHD showed personality characteristics that are related to self-regulation difficulties. The mediation analysis indicated that EF account for the association between Conscientiousness and inattention but not with hyperactivity-impulsivity. These findings are consistent with the notion that core dispositional personality traits  and executive control processes are related and work together to guide and self-regulate behaviors . MoreoveFrom a clinical perspective, and given the heterogeneity of ADHD, it is difficult to assign clear profiles of executive performance and personality traits in ADHD adolescents. Thus, clinical assessment of adolescents with ADHD should combine the use of EF and personality measures, which would make it possible to clarify clinically relevant issues at the level of normative and atypical cognitive and affective development. This could shed light on the factors that increase the risk of comorbidity in ADHD  and provide guidelines for the development of individually tailored treatments targeting executive proficiency and self-regulation skills. In addition, an understanding of the profiles of EF and personality traits in children and adolescents might lead to the identification of risks and protective factors that help to predict and improve long-term adult outcomes. Also, in terms of improving clinical communication, describing a patient in terms of personality traits may be clearer and more useful for clinical decision-making than describing him or her solely through diagnostic labels such as those used by diagnostic systems ,97,98. IThis study did have certain limitations that restricted its generalizability. A key limitation is the use of a cross-sectional design, meaning that it is impossible to demonstrate causality for the direction of the associations; therefore, caution must be taken when interpreting the results. A longitudinal, prospective study with more stringent testing would provide firmer conclusions about mediation. Furthermore, due to the complex nature of the etiopathogenetic pathways underlying ADHD, the most that we can infer is that the analysis of the directional relationships tested in our mediational model is only one approach among many other different levels of analysis in the search for a better understanding of the developmental pathways associated with ADHD during adolescence. Thus, it may be important in future research and replications to assess the age-related changes in this model across the lifespan. We also chose to examine a single model with four personality traits  as simultaneous independent predictors; we excluded Openness from the model because it has not been well validated in models of child temperament and personality. Therefore, it is possible that we did not obtain comprehensive characteristics of the structure underlying the personality traits during adolescence or of the Openness and EF associations, which further limits the generalization of our results. Additionally, our sample size and the percentage of participants in each of the groups (63.6% with ADHD and 36.4% controls) restricted our ability to fully understand the nature of the intergroup differences. Lastly, the ADHD group did not include individuals with hyperactive-impulsive ADHD presentations.Despite these limitations, to our knowledge, this is the first study to evaluate mediation effects in the relationships between the EF, FFM personality traits, and ADHD in adolescents. Although some studies have shown relationships between the FFM traits, EF and ADHD, the links remain unclear. This may be due to individual differences in personality traits and measuring instruments, as well as the heterogeneity in both executive profiles and ADHD symptoms. Our findings support the hypothesis regarding EF deficits and the configuration of the FFM personality traits in ADHD, building on previous research in terms of understanding the multiple causal pathways associated with the heterogeneity of ADHD. As such, the results suggest that a method combining the use of personality questionnaires, EF measures and rating scales of ADHD symptoms is probably helpful to improve the individual characterization of functional personality attributes  in ADHD S1 Table(DOCX)Click here for additional data file.


Attention deficit hyperactivity disorder (ADHD) is among the most frequent disorders within child and adolescent psychiatry, with a prevalence of over 5%. Nosological systems, such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and the International Classification of Diseases, editions 10 and 11 (ICD-10/11) continue to define ADHD according to behavioral criteria, based on observation and on informant reports. Despite an overwhelming body of research on ADHD over the last 10 to 20 years, valid neurobiological markers or other objective criteria that may lead to unequivocal diagnostic classification are still lacking. On the contrary, the concept of ADHD seems to have become broader and more heterogeneous. Thus, the diagnosis and treatment of ADHD are still challenging for clinicians, necessitating increased reliance on their expertise and experience. The first part of this review presents an overview of the current definitions of the disorder . Furthermore, it discusses more controversial aspects of the construct of ADHD, including the dimensional versus categorical approach, alternative ADHD constructs, and aspects pertaining to epidemiology and prevalence. The second part focuses on comorbidities, on the difficulty of distinguishing between “primary” and “secondary” ADHD for purposes of differential diagnosis, and on clinical diagnostic procedures. In the third and most prominent part, an overview of current neurobiological concepts of ADHD is given, including neuropsychological and neurophysiological researches and summaries of current neuroimaging and genetic studies. Finally, treatment options are reviewed, including a discussion of multimodal, pharmacological, and nonpharmacological interventions and their evidence base. With a prevalence of over 5%, attention deficit hyperactivity disorder (ADHD) is one of the most frequent disorders within child and adolescent psychiatry. Despite an overwhelming body of research, approximately 20,000 publications have been referenced in PubMed during the past 10 years, assessment and treatment continue to present a challenge for clinicians. ADHD is characterized by the heterogeneity of presentations, which may take opposite forms, by frequent and variable comorbidities and an overlap with other disorders, and by the context-dependency of symptoms, which may or may not become apparent during clinical examination. While the neurobiological and genetic underpinnings of the disorder are beyond dispute, biomarkers or other objective criteria, which could lead to an automatic algorithm for the reliable identification of ADHD in an individual within clinical practice, are still lacking. In contrast to what one might expect after years of intense research, ADHD criteria defined by nosological systems, such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and the International Classification of Diseases, editions 10 and 11 (ICD-10/11) have not become narrower and more specific. Rather, they have become broader, for example, encompassing wider age ranges, thus placing more emphasis on the specialist's expertise and experience.ADHD is defined as a neurodevelopmental disorder. Its diagnostic classification is based on the observation of behavioral symptoms. ADHD according to the DSM-5 continues to be a diagnosis of exclusion and should not be diagnosed if the behavioral symptoms can be better explained by other mental disorders .In the DSM-5, the defining symptoms of ADHD are divided into symptoms of inattention (11 symptoms) and hyperactivity/impulsivity (9 symptoms).In contrast, the ICD-10 classification distinguishes between hyperkinetic disorder of childhood  and hyperkinetic conduct disorder, a combination of ADHD symptoms and symptoms of oppositional defiant and conduct disorders (CD).Sluggish cognitive tempo (SCT) is a clinical construct characterized by low energy, sleepiness, and absent-mindedness, and is estimated to occur in 39 to 59% of (adult) individuals with ADHD.Emotion dysregulation is another associated feature that has been discussed as a possible core component of childhood ADHD, although it is not included in the DSM-5 criteria. Deficient emotion regulation is more typically part of the symptom definition of other psychopathological disorders, such as oppositional defiant disorder (ODD), CD, or disruptive mood dysregulation disorder .Whether emotion dysregulation is inherent to ADHD, applies to a subgroup with combined symptoms and a singular neurobiological pathway, or is comorbid with but independent of ADHD, is still a matter of debate , thyroid disorders, sleep disorder, drug interaction, anemia, and leukodystrophy.However, the picture is complex, as many differential diagnoses may also occur as comorbidities. For instance, bipolar disorder, which is frequently diagnosed in children and adolescents in the United States but not in Europe, is considered as a differential diagnosis to ADHD, but ADHD has also been found to be a comorbidity of bipolar disorder in 21 to 98% of cases.Clinical assessment in children should mainly be based on a clinical interview with parents, including an exploration of the problems, the detailed developmental history of the child including medical or psychiatric antecedents, information on family functioning, peer relationships, and school history. According to the guidelines of the National Institute for Health and Care Excellence (NICE) in the United Kingdom, this may also include information on the mental health of the parents and the family's economic situation. The child's mental state should be assessed, possibly using a standardized semistructured clinical interview containing ADHD assessments There is consensus that the diagnosis of ADHD requires a specialist, that is, a child psychiatrist, a pediatrician, or other appropriately qualified health care professionals with training and expertise in diagnosing ADHD.ADHD is related to multiple underlying neurobiological pathways and heterogeneous neuropsychological (NP) profiles. Twenty-five years ago, ADHD was characterized as a disorder of inhibitory self-control,Since then, other pathways have been added, such as time processing,A meta-analysis conducted in 2005 identified consistent executive function deficits with moderate effect sizes in children with ADHD in terms of response inhibition, vigilance, working memory, and planning.Nearly every neuropsychological domain has been found to be significantly impaired in ADHD compared with TD controls, though effect sizes are often small. This includes, for example, altered perception  for ADHD, that is, neurobiologically based impairments of NP performance characteristic of the disorder that may also be found in nonaffected close relatives. ADHD neuropsychological endophenotypes are assumed to mediate genetic risk from common genetic variants.Heterogeneity is found with regard to profiles, as well as with regard to the severity of cognitive impairment in individuals with ADHD, as measured by standardized tests. ADHD does not necessarily come with impaired neuropsychological test performance: about one-third of children with ADHD will not present any clinically relevant impairment, while another one-third shows unstable or partial clinical impairment, and about another one-third performs below average in NP tests. The classic concept of NP impairment, which assumes relative stability over time, possibly does not apply to NP deficits observed in ADHD, or only to a lesser extent. For the larger part, the manifestation of performance deficits may depend on contextual factors,Many studies have shown that behavioral ratings of ADHD symptoms or questionnaires on executive function deficits are not, or at best weakly, correlated with NP test performance, even when both target the same NP domain.It has been argued that symptoms defining ADHD may be understood as dimensional markers of several disorders belonging to an ADHD spectrum and, in consequence, the diagnosis of these behavioral symptoms should be the starting point for a more in-depth diagnosis rather than the endpoint.Neurophysiological methods like EEG, magnetoencephalography, and event-related potentials (ERPs) as task-locked EEG averages capture brain functions in ADHD at high (ms) temporal resolution. The approach covers both fast and slow neural processes and oscillations, and clarifies the type and timing of brain activity altered in ADHD at rest and in tasks. It reveals neural precursors, as well as correlates, and consequences of ADHD behavior.The EEG is dominated by oscillations in frequency bands ranging from slow δ (<4 Hz) and θ (4–7 Hz) via α (8–12 Hz) to faster β (13–30 Hz) and γ (30–100 Hz) band activity. The spectral profile reflects maturation and arousal, with slow frequencies dominating during early childhood and slow-wave sleep. Source models can link scalp topography to brain sources and distributed networks.Initial studies suggested a robust link between ADHD diagnosis and resting EEG markers of reduced attention, hypoarousal, or immaturity, such as increased θ and an increased θ/β ratio (TBR). However, more recent studies,During sleep, stage profiles reveal no consistent deviations in ADHD, but the slow-wave sleep topography is altered. In particular, frontal slow waves are reduced, leading to a more posterior topography as observed also in younger children.Task-related processing measures, particularly ERPs, have critically advanced our understanding of ADHD through their high-time resolution, which can separate intact and compromised brain functions. ERPs have revealed impairments during preparation, attention, inhibition, action control, as well as error, and reward processing, with partly distinct networks but often present during different phases of the same task. In youth and adults with ADHD, the attentional and inhibitory P3 components and the preparatory contingent negative variation (CNV) component are most consistently affected, but state regulation and error or reward processing are also compromised.Overall, the ERP results confirm attentional, cognitive, and motivational, rather than sensory or motor impairments in ADHD, in line with current psychological and neurobiological models. However, different ERP studies hardly used the same tests and measures, so valid statements regarding classification accuracy and effect size are particularly difficult,Despite published failures to replicate robust TBR based classification of ADHD, a TBR-based EEG test was recently approved by the U.S. Food and Drug Administration to assist ADHD diagnosis.This multistage diagnostic approach could possibly identify a homogeneous neurophysiological subgroup, but it omits critical elements of careful, guideline-based ADHD diagnostics. Reliability and predictive value of the TBR remain untested, and the increasing evidence for poor validity of TBR renders it unsuitable for stand-alone ADHD diagnosis. Accordingly, the use of TBR as a diagnostic aid was broadly criticized.In sum, the recent literature suggests that neither TBR nor other single EEG or ERP markers are sufficient to diagnose ADHD and are not recommended for clinical routine use, in line with the increasing evidence for heterogeneity in ADHD.Combining measures across time, frequency, and tasks or states into multivariate patterns may better characterize ADHD. The potential of such approaches is evident in improved classification using machine-learning algorithms based on combinations of EEG measuresFocusing on EEG-based prediction rather than diagnosis may hold more promise for clinical translation, and may utilize the EEG heterogeneity in clinical ADHD samples. For example, early studies on predicting stimulant response suggested that children with altered wave activity, in particular increased TBR, θ or α slowing, respond well to stimulant medication. However, in recent prospective work with a large sample, TBR was not predictive, and α slowing allowed only limited prediction in a male adolescent subgroup.Predicting response to intense nonpharmacological treatment is of particular interest given the high costs and time requirements. Promising findings have been reported for one neurofeedback study, where α EEG activity and stronger CNV activity together predicted nearly 30% of the treatment response.In conclusion, neurophysiological measures have clarified a rich set of distinct impairments but also preserved functions which can also serve as markers of persistence or risk. These markers may also contribute in the classification of psychiatric disorders based on neuromarkers (research domain criteria approach). As potential predictors of treatment outcome they may support precision medicine, and proof-of-concept studies also highlight the potential of multivariate profiling. The findings also demonstrate the challenge with this approach, including notable replication failures, and generalizability of most findings remains to be tested. Neurophysiological markers are not ready to serve as tools or aids to reliably diagnose ADHD, or to personalize ADHD treatment in individual patients.Modern brain imaging techniques have critically contributed to elucidating the etiology of ADHD. While MRI provides detailed insights into the brain microstructure, such as for example gray matter volume, density, cortical thickness, or white matter integrity, fMRI allows insights into brain functions through activation and connectivity measures with high–spatial resolution.U-shaped trajectories of maturation with a prepubertal increase followed by a subsequent decrease until adulthood while white matter volume progressively increases throughout adolescence and early adulthood in a rather linear way.The brain undergoes pronounced developmental alterations in childhood and adolescence. Gray matter volume and cortical thickness show nonlinear invertedSpecific functional networks, mainly those involved in inhibition, attention processes, cognitive control, reward processing, working memory, or during rest have been intensively studied in ADHD using fMRI in the past. Alterations have been reported in the corresponding brain networks and the main findings are summarized below.Resting state examines spontaneous, low frequency fluctuations in the fMRI signal during rest, that is , in absence of any explicit task.Meta-analyses summarizing the findings of functional activation studies report most consistent alterations in brain activation patterns as hypoactivation of the frontoparietal network for executive functions and the ventral attention system for attentional processes in children with ADHD.Emotion regulation and motivation is mediated by extended orbitomedial and ventromedial frontolimbic networks in the brain.Stimulant medication and neurofeedback studies have pointed to a certain normalization of dysfunctional activation patterns in critical dorsolateral frontostriatal and orbitofrontostriatal regions along with improvements in ADHD symptoms.To conclude, a wide range of neuroimaging studies reveal relatively consistent functional deficits in ADHD during executive functions, including inhibitory control, working memory, reward processes, and attention regulation but also during rest. Some of these alterations are more persistent, others are specific to children and may thus represent a developmental delay. Specific treatments showed trends toward a normalization of alterations in brain microstructure and functional networks.From family studies, as well as twin studies, the heritability for ADHD has been estimated to be between 75 upto 90%.In several studies, ADHD-related traits have also shown significant heritability. For example, in two independent, population based studies, significant single nucleotide polymorphism heritability estimates were found for attention-deficit hyperactivity symptoms, externalizing problems, and total problems.FOX2andDUSP6.Though ADHD was found to be highly heritable, the underlying genetic risk factors are still not fully revealed. The current consensus suggests, as in many other psychiatric disorders, a multifactorial polygenic nature of the common disorder. Both common genetic variants studied by hypothesis-driven candidate gene association or by the hypothesis-free GWAS could only reveal the tip of the iceberg. Through the candidate gene approach, only very few findings could show replicable significant association with ADHD, as reported by meta-analysis studies for the dopaminergic, noradrenergic, and serotonergic genes.A variety of national and international guidelines on the assessment and management of ADHD have been published over the last 10 years, not only for clinicians but also for patients and caregivers.According to the NICE Guidelines, the first step is always a planning process for the multimodal treatment with respect to the psychological, behavioral, and occupational or educational needs of the child and his/her family.Multimodal treatment approaches also advocate a systematic adaptive procedure that combines different treatment modules according to the needs and situation of the patient and family. This may, for instance, include a first stage in which parent counseling is initiated, a second-stage encompassing, for example, individual behavioral therapy for the child, while the parents participate in a parent training program in parallel, followed by a third stage in which stimulant medication is started, etc.All medication for ADHD should only be initiated by a health care professional with training and expertise in diagnosing and managing ADHD. The expert should be familiar with the pharmacokinetic profiles and bioavailability of all the short- and long-acting preparations available for ADHD. The following parameters should be considered before first medication: medical history of the child but possibly also of the parents, current medication, height and weight, baseline pulse and blood pressure, a cardiovascular assessment, and an electrocardiogram if the treatment may affect the QT interval. A cardiology expert opinion should be sought before starting medication for ADHD if there is a history of congenital heart disease, previous cardiac surgery, or a history of sudden death in a first-degree relative under the age of 40 years, or if the blood pressure is consistently above the 95th centile for age and height for children and young people.Treatment recommendations are often based on the specific needs of children, youth, or adults.In Europe, methylphenidate either as short- or long-acting preparation is the first-line medication for ADHD across the life span. Second-line medications are lisdexamfetamine, atomoxetine, and guanfacine. A switch to lisdexamfetamine is only recommended if children have first undergone at least a 6-week trial of methylphenidate at an adequate dose and have not derived sufficient benefit in terms of reduced ADHD symptoms and associated impairment, or if patients experience adverse side effects.According to the NICE guidelines, atomoxetine and guanfacine should only be offered if patients cannot tolerate methylphenidate or lisdexamfetamine or if their symptoms have not responded to separate 6-week trials of methylphenidate and lisdexamfetamine, having considered alternative preparations and adequate doses.2-adrenoceptor agonists, such as clonidine and guanfacine, regarding different aspects of effectiveness and tolerability.In the first “gold standard” study comparing the different treatment approaches for ADHD alone and in combination , the effects of both pharmacological therapy (methylphenidate and intensive counseling) and of multimodal therapy  were significantly more effective after 14 months than behavioral therapy alone or than the “standard” therapy  of the control group. The multimodal therapy was not significantly superior to pharmacological therapy alone, but did result in significant improvements in ADHD symptoms at a lower dosage of methylphenidate.The psychostimulants methylphenidate and amphetamine are the most effective agents for the treatment of core ADHD symptoms, with a favorable efficacy and adverse event profile.Following an adequate dosage of medication  and treAmong the most frequent side effects of psychostimulant therapy  are redCognitive behavioral therapy (CBT) is a form of behavioral intervention which aims at reducing ADHD behaviors or associated problems by enhancing positive behaviors and creating situations in which desired behaviors may occur. In the case of preschool and young school children, CBT focuses on parents and educators, who are instructed and trained to act according to CBT principles, while older children and adolescents may be trained directly to use more appropriate behavioral strategies.In cognitive training interventions, either PC-supported or in a manualized format, cognitive exercises that tap into cognitive domains, such as working memory or inhibitory control, are performed in a repetitive manner and with increasing difficulty. The evidence base for this type of intervention is poor according to recent studies , EEG activity measured by one or more electrodes applied to the head is transformed into a visual or acoustic signal and fed back online, for example, by a stimulus moving up and down. By steering the stimulus on the screen, the participant may gain control over his/her EEG activity. Many different training protocols have been applied to ADHD. Those which have received the best evaluation are the NF training of the θ/β frequency bands ratio  and the training of slow cortical potentials . However, “normalizing” an ADHD-specific deviant EEG pattern can no longer qualify as a meaningful goal, as no characteristic ADHD pattern seems to exist  and transcranial direct current stimulation (tDCS) represent other potential means to modulate cortical activity. Therefore, these approaches may also be promising in terms of improving clinical and cognitive ADHD symptoms such as inattention and impulsiveness.Mindfulness training, physical activity, and yoga seem to have positive effects on ADHD behavior, but for the time being, the scientific evidence is weak and these treatments are seen at best as complementary to other interventions.Follow-up studies have reported divergent results, with some reporting high rates of persistence until adulthood (up to 79%),


Psychostimulants and non-psychostimulants are the medications prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, several adverse results have been linked with an increased risk of substance use and side effects. The pathophysiology of ADHD is not completely known, although it has been associated with an increase in inflammation and oxidative stress. This review presents an overview of findings following antioxidant treatment for ADHD and describes the potential amelioration of inflammation and oxidative stress using antioxidants that might have a future as multi-target adjuvant therapy in ADHD. The use of antioxidants against inflammation and oxidative conditions is an emerging field in the management of several neurodegenerative and neuropsychiatric disorders. Thus, antioxidants could be promising as an adjuvant ADHD therapy. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioural disorder and is a chronic, often lifelong, condition ,2. The pThe pathophysiological mechanisms of ADHD are still not understood. However, biochemical, psychological, and environmental factors have generally been accepted as causes of the disorder. Several studies have suggested deregulation in catecholaminergic neurotransmission to be the cause ,12. MoreThe management of ADHD comprises multimodal treatments that include psychosocial and educational interventions . NeverthHowever, psychostimulants have been associated with side effects such as appetite loss, headache, stomach pain, agitation, sleep disturbance, anxiety, and insomnia ,20. MoreNeuroinflammation and oxidative stress play a role in the pathophysiology of ADHD due to genetic and environmental factors, catecholaminergic dysregulation, and medications used for treatment, all factors which could produce inflammation and oxidative stress, which increases the symptoms and, as a consequence, leads to establishing a vicious circle . Hence, Increasing evidence supports the role of neuroinflammation in the pathophysiology of ADHD . InflammIncreased ADHD symptoms have been reported in patients with an uncontrolled inflammatory environment. Thus, elevated levels of interleukin-6 receptor (IL-6R), RANTES  and tumour necrosis factor-α (TNF-α) in children with ADHD were associated with a major intensity of symptoms such as hyperactivity and inattention . MoreoveThe inflammatory mechanisms and the association of dysregulation in ADHD remain to be fully clarified but involve genetic and/or environmental factors. Several studies have reported an association between ADHD and the polymorphism of cytokines such as IL-2, IL-6 and TNF-α . HoweverSulforaphane (SFN) is found in highest concentrations in vegetables such as cauliflower and broccoli sprouts, and it has been shown that SFN is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2) . Nrf2 isSFN has been considered as a therapeutic target in several inflammation-associated diseases, including neurodevelopmental disorders such as psychosis and autism spectrum disorder ,57,58. AThe molecular mechanism by which SFN exerts its anti-inflammatory function is by inducing Nrf2 pathway activation, which contributes to the anti-inflammatory process by regulating HO-1 gene expression ,60,61. NInflammasomes are multiprotein complexes necessary for the release of pro-inflammatory cytokines (IL-1α and IL-18). Interestingly, it has been reported that SFN inhibited the activation of NLRP1, NLRP3, and NLRC4 inflammasomes ,67. HoweN-Acetylcysteine (NAC), a precursor of L-cysteine and the antioxidant glutathione (GSH), is found in plants, especially the onion ,97,98. N+/CD25+/FoxP3+) and interferes with the polarization of Th17 cells [Omega-3 fatty acids (omega-3 FAs) are polyunsaturated fatty acids, whose primary sources are in oily fish. They are components of neuronal membranes and have a main role in neurotransmission, neuronal development and function . Two of 17 cells ,79,80. I17 cells . However17 cells . Thus, fThere is increasing evidence for the involvement of oxidative stress in the pathophysiology of ADHD ,16, but On the other hand, it has been shown that dopamine and norepinephrine can easily undergo auto-oxidation, forming ROS ,126, whiRegarding ADHD medication, several reports have demonstrated that MPH has an impact on the generation of oxidative damage. Increases in DNA damage have been found mainly in the striatum of young and adult rats after MPH treatment . In specHence, the growing research in looking for alternative therapies for ADHD has focused on the neuroprotective effects of natural products as antioxidants because they may be high-efficiency alternative treatments with fewer side effects .As a consequence of oxidative stress, cells have the capacity to increase their antioxidant defences through the activation of Nrf2. Thus, Nrf2 pathway activation takes place to act against the accumulation of ROS. Consequently, Nrf2 activators have been proposed as antioxidant targets in neurodegenerative and neuropsychiatric disorders  to counteract the increase in oxidative stress ,139,140.In mice, the repeated administration of amphetamines induced decreases of dopamine and 3,4-dihydroxyphenylacetic acid DOPAC levels, as well as dopamine transporter immunoreactivity in the striatum, and such effects were significantly attenuated by the treatment with SFN . ActivatThe NAC molecule scavenges ROS and there has been growing evidence of its role in attenuating psychiatric and neurological disorders and associated pathophysiological processes such as oxidative stress, mitochondrial dysfunction and glutamate and dopamine dysregulation ,97,141. The omega-3 FAs supplementation can be an enhancer factor in the antioxidant defence against ROS  and has The association of ADHD with an increase in inflammation and oxidative stress could play a role in the pathophysiological process. Nowadays, ADHD has no therapeutic option able to counteract the progression of the disorder, and therapy with MPH and amphetamines might be increasing oxidative stress. Thus, all evidence points towards inflammation and oxidative stress as factors which are influencing ADHD, whereas antioxidants may perhaps be able to ameliorate ADHD progression due to their anti-inflammatory and antioxidant properties. Consequently, some of the antioxidants discussed in this review might establish a new therapeutic approach for the treatment of ADHD. While the use of natural antioxidants for diverse disorders has been considered as a safe and healthier approach for patients, they are still far from being standard treatments, due to the lack of controlled clinical studies that may well corroborate both their high efficacy and safety. Accordingly, better designed and more rigorous research and clinical trials are required before they can be established as a therapeutic alternative and further studies would also be necessary to corroborate the use of these antioxidants administered as a co-treatment with the current medications. Nevertheless, antioxidants could be considered as a multi-target adjuvant therapy for ADHD.


The aim of this study was to investigate the association between adult ADHD screening scores and hospitalization due to pedestrian injuries in a sample of Iranian pedestrians.Through a case-control study, a case population of 177 pedestrians injured by the vehicles in road traffic crashes were compared with 177 controls who lacked a record of intentional or unintentional injuries enrolled from various wards of Imam Reza University Hospital which is a specialty teaching hospital located in the same city with similar referral level. The cases and controls had an age range of 18–65 years and were matched on gender and age. ADHD symptom profile was assessed using the Persian Self-report Screening Version of the Conner’s Adult ADHD Rating Scales (CAARS-S:SV). The association of ADHD screening score and pedestrian injuries was investigated using multiple binary logistic regression to investigate the independent effect of ADHD index score on belonging to case group. Both crude and adjusted odds ratios were reported.p-value. The final multivariate analysis showed that variables associated with pedestrian injuries in the road traffic crashes were ADHD Index score ; economic status (including household income and expenditure capacity); educational level and total walking time per 24 h.Men comprised 86.4% of the study subjects. The crude odds ratios for all the four ADHD subscales to be associated with pedestrian injuries were 1.05, 1.08, and 1.04 for the subscales A (attention deficit), B (hyperactivity/impulsiveness) and ADHD index respectively. However, the association for subscale A was not statistically significant with a borderline Adult ADHD screening score can predict pedestrian injuries leading to hospitalization independently from sex, age, economic status, educational level and pedestrian exposure to traffic environment . According to World Health Organization, 1.27 million fatal road traffic injuries and 20–50 million non-fatal injuries occur as a result of road traffic accidents occur annually with a higher burden in low-and middle-income countries (LMICs) . PedestrRisk factors for moderate to severe injuries from road traffic accidents are comprised of human, environmental, and vehicle-related factors. Psychological/psychiatric factors have always been the focus of interest in field of road traffic injuries/accidents (RTAs). Attention deficit hyperactivity disorder (ADHD) is an important clinical condition mainly affecting children but also relatively common among adults . ADHD isSeveral studies including two recent reviews have been published showing an association between ADHD and various types of injuries both in childhood and adults. It has been shown that childhood ADHD increases the likelihood of injuries by 2.8 times and it has been shown that with ten units increment in the score of Hyperactive-Impulsive subscale of ADHD, leads to 73% increment in the chance of burn injuries . ADHD haSome characteristics of patients with ADHD could reasonably explain the association between ADHD and injuries. First of all, it could be the risk-taking behaviors that are much more prominent in ADHD. Risk-taking, which is a well-known predictor in road traffic injuries, could either increase the risks of other types of injuries such as falls or burns. Another feature is the attention deficit component of the disorder which is more prominently known risk factor for traffic injuries . Other mVarious studies have focused specifically on assessing the association of ADHD with traffic-related injuries. Some have considered investigating the association between ADHD with respect to victim’s role in road traffic environment . However, majority of the previous studies have been conducted on driving behavior or risk-of-crash among drivers with ADHD –20. The Those adults with a higher score on ADHD index, using Conner’s ADHD screening tool, could have higher likelihood of being injured and hospitalized due to pedestrian injuries in a sample of Iranian pedestrians.The potential association between pedestrian injuries and ADHD screening scores could vary with respect to the two types of attention deficit and hyperactivity/impulsiveness symptoms.Therefore, any assessment of the effect of ADHD on injuries should control for these factors, either through matching or multivariate analysis which is not the case with all the available evidence. The aim of current study was to investigate the following alternative hypotheses:This study employs a case-control design, and was conducted in two university hospitals of Tabriz University of Medical Sciences, located in in North-West of Iran. The study enrolled 177 pedestrians injured in road traffic accidents who were hospitalized during the years 2012–2013. Cases were patients receiving care from Shohada University Hospital located in Tabriz. The hospital is the regional trauma referral center in East Azerbaijan Province. Inclusion criteria for cases included people who had been hospitalized for 24 h or more in Shohada University Hospital due to pedestrian injuries in road traffic crashes, Patients were recruited from both genders. All patients lived in East Azerbaijan Province, and ranged 18–65 years of age. Exclusion criteria from the study included patients who were injured in other accidents, intentional injuries, patients who died before hospital admission, and those who were unable to respond due to severe injury. Of the 182 potential recruits to this study, five patients declined to participate.For this study’s control group, 177 patients were enrolled from various wards of Imam Reza University Hospital which is a specialty teaching hospital located in the same city with similar referral level. This hospital serves as a referral center for the province, serving the same geographic population as Shohada Hospital for most admissions. Selecting controls was done according to the principals described by Wacholder et al. . For insThe collected information was categorized in three separate data group areas.Bachelor and master degrees equivalent to the ISCED levels 6 & 7Associate degree (ISCED level 5)Middle school & high school Illiterate and elementary equivalent to ISCED levels below 2.First category included background and demographic characteristics such as sex, age, marital status, education level, job, economic status, average walking (distance or time) in daylight and night time, and the type of injuries incurred to pedestrians over accidents. Marital status was defined as married (based on Iranian legislations) and single . The educational level according to Iranian educational system was defined as an ordinal variable including four categories and were reported along with their equivalents in terms of the International Standard Classification of Education (ISCED) which is a statistical framework for organizing information on education maintained by the United Nations Educational, Scientific and Cultural Organization (UNESCO) . The catFor assessing the economic status two indicators were used as household income and self-rated expenditure capacity. Self-rated expenditure capacity is a validated tool assessing the expenditure capacity through six components including clothing expenditure, fruit foods expenditure, other food expenditure, jewelry and prestige expenditure, Traveling expenditure, and education expenditure each measured through a 5-point Likert scale summing to form the “self-rated expenditure capacity” , 48. In Second category included environmental factors, including places and times where injuries occurred. The third category of formation addressed the ADHD symptoms obtained through structured clinical interviews using the screening version of the Conner’s Adult ADHD Rating Scale (CAARS), which assesses ADHD symptoms using 30 questions. It utilizes a 4-point Likert-scaled answer format in which respondents are asked to rate items pertaining to participant’s problems. The validity and reliability of CAARS as a screening instrument is in accordance with DSM-IV guidelines . Screening included several CAARS subscales as; attention deficit index ; hyperactivity-impulsivity index  with 9 items; and ADHD index with 12 exclusive items.The structured clinical interviews also included questions based on criteria for ADHD derived from the DSM-IV translated from English to Persian with slight adjustments for questions to be understandable and acceptable for the Iranian patients. The self-report screening version of the Conner’s Adult ADHD Rating Scales (CAARS-S:SV) and Observer Screening Version of the Conner’s Adult ADHD Rating Scales (CAARS-O:SV) have earlier been translated and validated in Persian in 2012–2013.Internal consistency of the Persian version of both the CAARS-S: SV and CAARS-O: SV using Cronbach’s alpha for all four subscales have been within a range of 0.82–0.97. Content validity of the Persian versions of CAARS-S:SV and CAARS-O:SV was confirmed by the adjusted kappa of over 0.76 for all items comprising the CAARS-S:SV and CARRS-O:SV .The questionnaires were completed by the same trained interviewers for cases and controls through face to face interviews in illiterates. People with enough literacy self-administered this scale.In these cases, questionnaires were checked  by the interviewer. To increase the inter-rating agreement, the interviewers passed a training course; used standardized data collection procedure; the data collection activities were monitored; and the study specific aims were masked as recommended before .The data were collected continuously during May 2012 to April 2013 to reach adequate sample size. The sample size was estimated through the pilot phase, comparing the mean ADHD index scores of 9.7 and 8.3 respectively for cases and controls and corresponding standard deviations of 4.83 and 4.55 respectively. A maximum 5% type 1 and 20% type 2 errors were assumed for power estimation. The sample size calculation was made using SAMPSI function in Stata statistical software package. Cases were matched through frequency matching method. In this kind of matching process, matching is not applied individually and it is conducted for groups of subjects. That is to say a group of controls is matched to a group of cases with respect to a given characteristic such as age or sex in current study. For instance, if in a case-control study with 100 cases where there are 40 males and 60 females, we would select a control group having the same gender distribution. Frequency matching is useful when the distribution of cases for a confounder differs markedly from distribution of that variable in source population which is the case with both sex and age in current project.P-values below 0.05 were considered as statistically significant.Descriptive statistics were provided for background variables separately in case and control groups. For comparison of the association of the risk factors with injury among groups, the independent t and Mann-Whitney tests were used according to the distribution of the data. For the categorical variables, Chi-Square and Fisher Exact tests were used. Crude and adjusted Odds Ratios (ORs) with 95% Confidence Intervals (CI) were reported. To investigate the potential independent predictive role for ADHD scales and exploring other determinants of hospitalization due to pedestrian injuries, multiple binary logistic regression analysis was used. Injury group membership was considered as dependent variable in bivariate and logistic regression analysis. Taking into account the main purpose of the current study and the inherent collinearity between various ADHD subscales, the final multiple regression models were developed using only the A, B and D subscales of the screening tool through three separate models. However, the first model that included D-subscale answers to the main research question of an association between ADHD and pedestrian injuries. D-subscale at same time has the highest sensitivity and specificity in detecting adult ADHD disorder regardless of the disorder subtype . The data were analyzed using the Stata version 13 statistical software package . The study protocol was approved by the institutional ethics committee in Tabriz University of Medical Sciences. Written informed consent was obtained from all participants after explaining the aim of the study.Here we present some background information to have a better understanding of the study sample including cases and controls. Pedestrian injury victims, equaling 177 patients, were compared with 177 appropriate controls. Men comprised 86.4% of all the study subjects. Mean age of the participants was 39.7 years with a standard deviation of 14 years. Males comprised 306 (86.4%) of participants and there were 48 (13.6%) females injured. Some demographic characteristics for cases and controls are demonstrated in Table Mean walking times in day and night were compared for the cases and controls and it was found that the mean walking time was significantly higher for cases than controls both during the day and night Table .Table 2Hits by motorized vehicles caused 43.50% of victims to be injured at lower extremities and 31.64% of them had more than two organs injured. The majority of accidents (59.32%) had occurred in 2-lane roads. Most accidents (37.30%) occurred between 6 A. M (Ante Meridiem) to 12 P. M (Post Meridiem). Majority of the crashes (80.8%) occurred on weekdays (Saturday-Wednesdays) compared to 19% occurring on weekends.p-value of 0.08.In order to identify potential confounders of study hypothesis to be controlled later through multivariate analysis, using bivariate analysis methods, here we investigated co-variation of study variables with being hospitalized due to pedestrian injuries as the outcome variable. Table The main research question is answered in this section showing the independent association of ADHD scale scores with the outcome variable while controlling for potential confounding effects of other cofactors. Three final regression models were developed to answer the research questions including five regressors as independent determinants of pedestrian injuries. Each of the three models included the three ADHD subscales as attention deficit subscale, hyperactivity/impulsiveness subscale and ADHD index score respectively. Table As could be found in Table Injury group membership was considered as dependent variable logistic regression analysis.The present study revealed that pedestrians who had road traffic injuries leading to hospitalization, were more likely to have higher scores on ADHD symptoms. As about 40% of mortalities due to RTAs in East Azerbaijan (the study setting) occur either at the crash scene or on the way to the hospital, it was not possible to include these victims due to lack of the interview potential. We didn’t find any publication to report an association between ADHD and severity of RTAs leading to higher pre-hospital death proportion among crash victims with ADHD than those without it. If no such an association is assumed, our results may also have some generalizability to RTAs regardless of injury severity. Otherwise, if we assume that people with ADHD are either more or less likely to have injuries with higher severity than victims without the disorder, an under-estimation or over-estimation of the odds ratio of ADHD scores in our cases may be expected for extrapolation of results further than hospitalized pedestrian injuries.52). As measured by Conner’s adult ADHD screening D-index scores, the present study revealed that pedestrians who had road traffic injuries leading to hospitalization, were more likely to have higher scores on ADHD symptoms.. ADHD may affect the pedestrian crash risk by various mechanisms related to the two main features of ADHD i.e. attention deficit and hyperactivity/impulsiveness symptoms. The psychodynamic approach, the cognitive approach, and the character and human motivation approach are earlier discussed as explanations for risky behavior among young people. The sensation-seeking theory is reported to be the most relevant and plausible link with ADHD and risk-taking motorcycle riding behaviors [The three most important types of injured road users in traffic environment that may be affected by symptoms of ADHD include; drivers , riders (motorcycle and bicycle riders) and pedestrians. The current study is among the very few studies that have specifically investigated an association between ADHD symptoms and risk of pedestrian crash. The association between pedestrian injuries and ADHD is largely ignored in literature and we retrieved one article specifically investigating the ADHD in pedestrian safety as well as two other simulator studies –54. The ehaviors , 55. Thiehaviors .The higher likelihood of traffic injuries in pedestrians with ADHD, if also confirmed through future cohort studies, may be explained through distraction not just due to the main attention deficit symptoms of ADHD. For instance, it has been shown that people with ADHD are more likely to use cell phones for a longer time , may be Although, evidence on adult pedestrian safe walking behavior in subjects with ADHD is quite scarce, simulation study on children playing the pedestrian role in simulation environment showed that children with combined type ADHD, prefer to choose riskier environments to cross within, the shorter amount of time left to spare upon reaching the other end of the cross walk, and the increased frequency of hits/close calls they experienced . ProfessIn our study, individuals with lower economic status, as assessed by household income and self-rated expenditure capacity, were more involved in road traffic accidents leading to hospitalization than controls. Household income and the primary carer’s education level are shown to be inversely related with child pedestrian injury risks . Althoughttps://safety.tbzmed.ac.ir/page/54/PREC.html) has been started and fortunately has included ADHD related measurements. However, it may take half a decade to gain accurate data from such cohorts and we need to consider the evidence from currently available studies. The present study used a case-control design. Like all other case-control studies, the potential for various biases should always be taken into account. The most important type of bias needing to be minimized is selection bias. “Selection bias exists when cases or controls are selected in a way that is not representative of the respective exposure distributions in the study base.” [Implications: We explored the association of ADHD score with pedestrian injuries in a given population in Iran. Due to paucity of information in this area, we don’t exactly know whether the study setting can modify the effect of ADHD scoring on such an association assuming that the whole picture of traffic behaviors including drivers, riders and pedestrians as well as the infrastructural safety may affect the crash risk and interact with its determinants including ADHD. At the same time the results based on association of ADHD symptom scores with traffic injuries puts forward a hypothesis that those with higher symptom scores even if not diagnosed to have ADHD may have higher likelihood of injuries than those with lower scores. How severe injuries might have impacted cognitive function that affects the assessment for ADHD symptoms is a concern that we raise in the current study. Two aspects of this could be considered. First is that head injuries may also be an etiology  and secondly the information bias that may be caused by impaired cognitive function. These should be interpreted accordingly. This could be reliably addressed in cohort studies that measure about ADHD along with other pedestrian injury risk factors. Such cohorts are quite rare worldwide. Recently the Persian Traffic Cohort which is a population-based road safety specific population cohort  may be an effective way to reduce accidents. The current case-control study was planned based on mechanism of injury not the type of injury. There have been several studies conducted focousing on type of injury, such as head injuries or burn injuries, rather than mechanism of injury such as traffic injuries or fall injuries. Actually there seems to be more plausible for ADHD to affect specific mechanisms of injuries rather than specific types of injuries. It may be interesting for future research to consider parallel assessment of this issue. Although, in case of pedestrian injuries it may not be a major problem, it should be appropriately addressed with respect to motorcycle driver injuries. This is because, the pattern of injuries among motorcyclists is substantially different from other traffic accidents and at the same time choosing to travel with a motorcycle may be considered in some cases as a risk taking behavior or determined by socioeconomic level both of which are associated with having ADHD. However, being a pedestrian is a common traffic role that nearly everyone with a normal life owns.In present study, our methodology didn’t permit us and we didn’t aim to prove a causal association of clinically diagnosed ADHD and pedestrian injuries. Instead, we investigated a potential predictive role for ADHD scores based on self-reporting. This was the reason we, unlike some similar previous studies, avoided using terminologies such ad risk factors or causal relationship neither in our findings or conclusions. We just tried to discuss the plausibility of such an association for screening purposes and hypothesis generation for future studies. However, findings of present research, as presumably the first non-simulation case-control study specifically on adult ADHD symptoms and pedestrian injuries, puts forward implications for future research on parallel use of clinical diagnosis and self-report scales. Additional limitations that could also be noted include the lack of a full ADHD diagnosis along with the collateral (other) reports of ADHD symptoms. One more limitation of this study is that the authors did not exclude based on diagnoses or medications known to have impact on executive functions or cognitive control.Adult ADHD screening score can predict pedestrian injuries leading to hospitalization independently from sex, age, economic status, educational level and pedestrian exposure to traffic environment . This can provide hints towards pedestrian safety promotion in public health and clinical practice as well as implication for designing future research. For instance, surgeons noticing some symptoms among injured pedestrians should consider an ADHD screening or psychological consultation. Similarly, psychiatrists visiting patients with adult ADHD should inform them about potential risks of pedestrian injuries. Adult ADHD screening may be considered at research or policy levels for given target groups such as relatives of children with ADHD.


It is well known that a wide range of psychiatric disorders co-occur with attention deficit hyperactivity disorder. In this study we aimed to examine the associations of psychiatric comorbidity in ADHD with symptom severity and level of functioning.We used data from the Swedish National Quality Registry for ADHD Treatment Follow-up and identified comorbid diagnoses in a sample of 3246 Swedish children and adolescents with ADHD. We investigated the association of comorbidity with symptom severity and level of function by multiple linear regressions.Autism spectrum disorder, anxiety and affective disorders, oppositional defiant disorder or conduct disorder, learning disorders, and multiple comorbid disorders associate to lower levels of functioning compared to ADHD only. Multiple comorbidity, autism spectrum disorder, oppositional defiant or conduct disorders and tic disorders relate to ADHD symptom severity.Comorbidity subgroups with ADHD differ in functional impairment and ADHD symptoms severity. Information on comorbidity profiles could be used for treatment planning more adapted to the individual. Especially those who have autism spectrum disorders and multiple comorbid disorders are at risk of severe ADHD symptoms and low level of functioning. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention and/or hyperactivity and impulsivity causing impairment in two or more settings. DSM-5 classifies three subtypes: inattentive presentation, hyperactive-impulsive presentation, and combined presentation. For a diagnosis of ADHD, symptoms should have manifested before 12 years of age and persisted for a minimum of 6 months [ADHD is associated with an increased risk of having other coexisting psychiatric disorders, both in childhood and in adulthood . ComorbiCommon childhood ADHD comorbidities are oppositional defiant disorder (ODD) and conduct disorder (CD) , learninResearch indicates that patients with serious mental disorders have comorbidity as a common factor . ComorbiWe do not fully understand the clinical impact of comorbidity in ADHD. The present study will provide an overview of common comorbid diagnoses and comorbid combinations in a large sample of children and adolescents with ADHD, who have contact with psychiatric services in Sweden. We assessed the association of comorbidity with clinical ratings of global psychosocial functioning. In addition the association of comorbidity with severity of ADHD symptoms was assessed. We hypothesized lower global psychosocial function in individuals with comorbidities, especially multiple comorbidities. We also hypothesized that ODD/CD is related to the dimensions of ADHD and that it results in more severe ADHD symptoms than in individuals with ADHD only.Participants in the study were identified through the Swedish National Quality Registry for ADHD Treatment Follow-up (BUSA). BUSA is an internet-based quality assurance register whose target population is all Swedish individuals with a confirmed ADHD diagnosis according to ICD-10 (F90.0–F90.8). However, BUSA is a non-mandatory registry and patients can decline participation. Thus, only a subset of individuals with ADHD is included. The registry holds individualized information on demographics, comorbid diagnoses, pharmacotherapy and other treatment interventions, and ratings of symptoms by clinicians, parents, teachers, and the individuals with ADHD themselves . All patBUSA offers an opportunity to study comorbidity in a large group of individuals with ADHD diagnoses, although this is not the primary aim of the registry. We analyzed data from the revised latest version of BUSA (applied from 2016), consisting of registrations from the period 14 January 2016 to 20 December 2017. All registered individuals under 18 years of age were included in the study  , and sevThe CGAS is a clinician-rated scale of global functioning in children and adolescents, it measures global functioning as a single factor. The CGAS can be used to rate the level of global functioning in children and adolescents from 4 to 20 years of age. The scale ranges between 1 and 100, with 1 representing the lowest level of functioning. A clinician rates the level of global functioning during the past month, at home, in school, and with friends. The scale is divided into 10-point intervals with a verbal description for each interval. The psychometric properties of the CGAS show moderate reliability . The CGASNAP-IV is a parent- or teacher-report screening of ADHD symptoms in children and adolescents. In this study, parent ratings were used. It rates the severity of current symptoms on a scale from 0 to 3. Higher scores indicate greater levels of ADHD symptoms. The Swedish version used in BUSA comprises 30 questions. Items 1–9 correspond to inattention criteria in DSM-IV. Items 11–19 correspond to the criteria for hyperactivity and impulsivity, and items 21–28 are questions on ODD. Item 10 is a summary score for attention deficit, and item 20 is a summary score for hyperactivity and impulsivity. Item 29 is a DSM-III-related item on ODD, and item 30 is a summary score for ODD. Test–retest reliability for SNAP-IV is evaluated as .66–.92 , and int2 = .556, p = .46) or in gender . There was less comorbidity , in the group with missing CGAS data. For SNAP -Total (2391 with missing data and 855 with data), there were no differences in gender  or age group, χ2 = .18, p = .67). The missing-data group had less registered comorbidity .Some patients in the registry had incomplete data. Some types of data, for example, scale measurements, were missing. Analyses of missing data showed no differences between those with CGAS data (n = 2043) and those without (n = 1203) in age  We tested the assumptions for linear regression, that is, linearity, normality of residuals, and equality of variances. The P plots of standardized residuals showed normally distributed residuals with roughly equal variance. We analyzed the influence of comorbidity on CGAS scores, on SNAP-IV total scores, and on SNAP-IV subscale scores; inattention and hyperactivity/impulsivity. All associations were assessed by multiple linear regressions. Comorbid diagnoses, gender, and age were independent variables. Overall functioning (CGAS) and ADHD symptom severity  were dependent variables in separate analyses. We ran the analyses in IBM SPSS Statistics for Windows, version 22.0 .Of the 3246 included participants, the majority, 65.2%,  were diagnosed with combined ADHD (mean age 12.14 ± 2.86 years), followed by 18.4% with the inattentive type , the hyperactive/impulsive type 4.4%,  and 3.4% were diagnosed with ADHD not otherwise specified . The proportion of missing data on ADHD subtype was 8.6%. Approximately 38% of the total sample were female. The largest group 51.8% were in the age range 13–17 years, the mean for the total group was 12.5 ± 2.9 years (range: 4–17 years).Table 2 = 14.84, p = < .001) and tic disorders . Girls were more likely to have anxiety disorders , affective disorders , and multiple comorbidity . There were no gender differences in learning disorders or ODD/CD. A chi-squared test comparing frequencies of single comorbidity in a younger group 4–12 years, and an older group 13–17 years showed a significant interaction effect for ASD and age: the younger group was more likely to have ASD  and ODD/CD . The older group was more likely to have anxiety disorders , affective disorders , and multiple comorbid disorders, . There were no associations between age and learning disorders or between age and tic disorders.In the total sample, 44.5% had one or more of the six diagnoses that were investigated. Table CGAS was regressed on the comorbid disorders and demographic variables gender and age, with no comorbid disorder as reference Table .Table 2MGender had no effect on CGAS scores, but age was significantly and positively associated with higher CGAS. On average, CGAS scores were .88 points higher for every year of age, or 8.8 points for 10 years, thus the older patients had less functional impairment.All comorbid disorders except tic disorders were significantly and negatively associated with CGAS. Children and adolescents with these disorders had from (on average) − 10.99 (multiple comorbidity) to − 2.99 (learning disorders) CGAS scores compared to children with ADHD alone.We also investigated whether comorbidity was associated with severity of ADHD symptoms, as measured by the SNAP-IV subscales: total (T), inattention (I), and hyperactivity/impulsivity (H). The independent variables were the same as in the first regression analysis Table .Table 3MThe effect of gender on SNAP-IV inattention subscale score was significant (boys had on average higher scores of inattention than girls). Age was associated negatively with all ADHD scales, , demonstrating more severe ADHD symptoms among the younger patients.Multiple comorbidity and ASD were positively associated with all subscale scores of SNAP-IV, meaning more inattention and hyperactivity/impulsivity symptoms in the presence of multiple comorbidity and ASD. ODD/CD and tic disorders were positively associated with SNAP-IV total scale.We aimed to examine the associations of comorbidity with global level of functioning and with severity of ADHD symptoms. The results for the influence of comorbidity on global functioning confirm our hypothesis that comorbidity is associated to reduced functioning, this align with prior research that showed a strong relation of comorbidity to low functioning e.g. work disability or substantial limitation in functioning due to comorbidity of mental disorders . Those wThe results revealed that the presence of ASD, multiple comorbidities ODD/CD and tic disorders is also associated with more ADHD symptoms in this sample of children and adolescents with ADHD. Similar finding of significantly higher SNAP-IV total scores (parent ratings) for ADHD with comorbid ODD/CD compared to ADHD only and compared to ADHD + anxiety was found in an MTA study  supportiThe association of age with better global functioning and less ADHD symptoms found in this study is interpreted as a result of parents seeking psychiatric help for younger children when they have more severe symptoms, compared to seeking help for older children also when they have milder symptoms.The association between ASD and ADHD symptoms was not foreseen. We hypothesized more severe ADHD symptoms in individuals with comorbid ODD/CD, and this was confirmed. The co-occurrence of ASD and ADHD involves a complex pattern and quality of symptoms, and impaired attention and impulsivity may in some cases originate in ASD rather than in ADHD . It may There is an intricate interplay between ADHD symptoms and symptoms from comorbid diagnoses. As an example a depression might influence the core symptoms of ADHD and worsen inattention as compared to when the depressive symptoms are not concurrent. Other diagnoses can add symptoms beyond the core symptoms of ADHD. For example ASD can cause more severe global functional impairment. The results of this study provide information on comorbid diagnoses and level of functional impairment and associations to ADHD symptoms, but the results do not reveal the mechanisms that may underlie the differences in associations among the disorders.The estimated world prevalence in children and adolescents of any anxiety disorder is 6.5%, any depressive disorder 2.6%, and any disruptive disorder 5.7% . These eConcurrent ADHD and ASD as well as multiple comorbidities pose a challenge for finding the best treatment strategies. More complicated planning of pharmacological and non-pharmacological treatment and follow-up can be assumed. However, the recommendations for pharmacological treatment in children and adolescents with ADHD and comorbid ASD are in line with guidance for treatment in ADHD alone . The cliWe were limited to the documentation in the registry, with no way to control the information other than checking for impossible values. The CGAS score is based on the clinician’s judgement, and we cannot exclude information bias to some degree.The study was conducted in the context of clinical every day practice, and the generalizability of our results to the population of children and adolescents with ADHD diagnoses in Sweden is limited to the group who have contact with psychiatric services and consequently more severe problems. There can also be qualitative differences between those who were asked to participate in the registry and those who were missed. However, we have no reason to believe that there are any systematic differences between these groups. A more likely source of selection bias is differences between those who agreed to participate and those who declined: it is possible that those who agreed to participate did so in part because they had more severe problems than those who declined, thus representing a particular subgroup of all children and adolescents with ADHD.Frequency and regression analyses included six common ADHD comorbid disorders, but the effects of other disorders were not assessed. Finally, the results are cross-sectional and we cannot assess causality.Despite missing registrations, a strength of this study is the sample size. The included patients came from a range of units and there is a national coverage of ADHD patients, resulting in a fair representation of young patients with ADHD who are receiving psychiatric care.ADHD in combination with multiple disorders, ASD, ODD/CD, anxiety, affective and learning disorders in decreasing order, were associated to low level of global functioning compared to ADHD only. ADHD with multiple disorders, ASD, ODD/CD and tic disorders were associated with more ADHD symptoms. Gender was not associated to the level of functioning, but there was an association to severity of inattention symptoms with boys having more inattention problems. Due to the impact of coexisting psychiatric disorders on clinical measures, the individual comorbidity profile should be taken into account in treatment plans for ADHD.