Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. ADHD can affect the individual, the individual’s family, and the community. ADHD is managed using pharmacological and nonpharmacological treatments, which principally involves others helping children and young people (CAYP) manage their ADHD rather than learning self-management strategies themselves. Over recent years, technological developments have meant that technology has been harnessed to create interventions to facilitate the self-management of ADHD in CAYP. Despite a clear potential to improve the effectiveness and personalization of interventions, there are currently no guidelines based on existing evidence or theories to underpin the development of technologies that aim to help CAYP self-manage their ADHD.The aim of this study was to create evidence-based guidelines with key stakeholders who will provide recommendations for the future development of technological interventions, which aim to specifically facilitate the self-management of ADHD.A realist evaluation (RE) approach was adopted over 5 phases. Phase 1 involved identifying propositions (or hypotheses) outlining what could work for such an intervention. Phase 2 involved the identification of existing middle-range theories of behavior change to underpin the propositions. Phase 3 involved the identification and development of context mechanism outcome configurations (CMOCs), which essentially state which elements of the intervention could be affected by which contexts and what the outcome of these could be. Phase 4 involved the validation and refinement of the propositions from phase 1 via interviews with key stakeholders . Phase 5 involved using information gathered during phases 1 to 4 to develop the guidelines.A total of 6 specialist clinicians, 8 parents, and 7 CAYP were recruited to this study. Overall, 7 key themes were identified: (1) positive rewarding feedback, (2) downloadable gaming resources, (3) personalizable and adaptable components, (4) psychoeducation component, (5) integration of self-management strategies, (6) goal setting, and (7) context . The identified mechanisms interacted with the variable contexts in which a complex technological intervention of this nature could be delivered.Complex intervention development for complex populations such as CAYP with ADHD should adopt methods such as RE, to account for the context it is delivered in, and co-design, which involves developing the intervention in partnership with key stakeholders to increase the likelihood that the intervention will succeed. The development of the guidelines outlined in this paper could be used for the future development of technologies that aim to facilitate self-management in CAYP with ADHD. Attention deficit hyperactivity disorder (ADHD) is a highly comorbid  neurodevADHD management includes a combination of behavioral and pharmacological interventions . There iPeople with long-term conditions (including ADHD) spend around 1% of their time interacting with a clinician, leaving 99% of their lives managing their condition themselves . HoweverThe promotion of safe quality care; any self-management intervention for CAYP with ADHD will need to adhere to quality standards to ensure the content is reliable and appropriate.Support should be based on evidence and what the patient’s needs and preferences are; if the intervention does not adhere to what the patient wants or needs, the patient may be less likely to engage with it.Self-management support should be provided to help patients manage their health and care; CAYP with ADHD should self-manage their condition to decrease the likelihood of them falling into crisis later in life.Community resources should be available to improve access; resources should be available to facilitate and support the self-management of ADHD in CAYP.Capability Opportunity Motivation-Behavior (COM-B) model, which refers to the interactions among “Capability,” “Opportunity,” “Motivation,” and “Behavior.” Capability refers to the psychological and physical ability to engage with an activity, opportunity refers to factors outside of the individual to ensure behavior change is possible, and motivation refers to brain processes that “energize and direct behavior.” The COM-B model provides a useful framework of elements that influence behavior change and can indeed be applied to self-management. For example, to self-manage a condition, the individuals’ behavior will need to change. To do this, they should be motivated and have the capability to change their behavior and be in the correct environment for the change to occur.Similarly, the Behavior Change Wheel (BCW)  providesFurthermore, the Health Foundation states that people with long-term conditions need to have the knowledge, skills, and confidence to manage their condition “effectively in the context of...everyday life” . These uTechnology has been shown to have a large potential to improve the effectiveness and personalization of mental health interventions . A numbeThe results of these interventions have found an increased ability to remain on task at school , improveHowever, not all of these studies show positive or significant results. ADHD is a highly complex comorbid condition and it is therefore difficult to control for contextual differences using randomized controlled trial (RCT) methodologies. It is also possible that the uptake of each intervention among participants may vary . Others It is now understood that the steps taken for increasing evidence in complex conditions is no longer linear, and the updated Medical Research Council (MRC) Framework (2008)  places gA total of 3 key components for the development of these complex interventions are outlined below:Interventions should be clearly underpinned by existing theories. Theories that are based on existing knowledge can offer a clear way to underpin a rationale, which can assist with communication with stakeholders ,46.Interventions should be developed in partnership with key stakeholders -48.Intervention developers should account for the context by which the intervention is developed by identifying what works for whom and under what circumstances. This means the intervention is more likely to be a success ,43,49..Other evaluation study designs such as RCTs and quasi-experimental studies only answer the question “What works?” and do no capture the complexity of complex conditions and interventions or the characteristics of the context in which the intervention is delivered . This isTherefore, this study aimed to utilize an RE methodology  and invoRE has been shown as an effective framework for evaluating complex health interventions . The aimThe 5 stages of this study are as described in the following sections:Propositions are comparable with that of hypotheses that predict what is believed to occur in a given situation or within research. Developing the propositions for this study involved authors LP and JP exploring theoretical concepts from the literature that derives from behavior change and human-computer interaction theories see  that couUsing the principles of RE , a theorAfter the propositions (Stage 1) and the theoretical framework (Stage 2) were developed, they were set out as context mechanism outcome configurations (CMOCs) during Stage 3 of this process. Authors LP and JP generated the CMOCs. CMOCs were then validated and refined by conducting interviews with CAYP with ADHD, their parents/carers, and specialist clinicians. Author LP conducted the interviews and they were conducted at the participant’s convenience. Clinician interviews were undertaken at the clinicians’ workplace and young persons’ and parents’ interviews took place in their homes.Participants were recruited to adhere to the sampling frame below.CAYP with ADHD and their parents/carersMales and femalesCAYP with autism spectrum disorder (ASD) and without ASDFamilies who live in the 10% of most and least deprived areas of the United Kingdom CAYP with ADHD aged 8 to 11 yearsCliniciansA sample that includes ADHD specialist nurses, a pediatrician, and a psychiatrist.Clinicians who work at Child and Adolescent Mental Health services and pediatric neurodisability services.CAYP with ADHD and parents/carers were recruited via a database held by the research team. Clinicians were recruited via the National Health Service (NHS) in the South Yorkshire region. Participants were recruited until data saturation was achieved . The eliSemistructured interviews focused on initial propositions that were tested and refined. CAYP with ADHD, their parents/carers, and clinicians provided interview data to test the propositions. The study received ethical approval from the University of Sheffield’s School of Health and Related Research Ethics Committee (Ref: 021203) and received NHS Health Research Authority and Research and Development local approval. Interviews took place in the CAYP/parents/carers’ homes and clinicians’ workplaces. All participants provided written informed consent or assent (CAYP only).Participants were asked (age appropriate) questions that were derived from the propositions. Questions included the following:What type of feedback do you think your child would like and why? (parent/carer)What do you think the role of friends and family could be for supporting CAYP with ADHD with a technological intervention? (clinicians/parent/carer)If you play a computer game, do you like to collect things like coins, stars, points? (CAYP with ADHD)Parents/carers provided ADHD medication details for their child (where applicable) and completed a Swanson Nolan and Pelham IV questionnaire to provide a measure of their child’s current ADHD symptoms.Analysis focused on refining and generating new CMOCs. Principles of thematic and framework analysis were adopted ,68. GuidThis was based on the refined and newly generated CMOCs from Stage 4. The final guidelines aim to provide a set of recommendations for designing a complex technological intervention that aims to help CAYP with ADHD self-manage their condition. The guidelines also provide advice regarding the environment in which the intervention should be delivered. The CMOCs refined during Stage 4 were used to form the content of the guidelines. The guidelines can be found in A total of 21 participants  were recruited from July 2018 to October 2018. Participant demographic information is included in Overall, 9 propositions were identified by author LP and checked for accuracy by author JP. They were then tested against the interview data and refined:If the user receives feedback from the intervention, then the user’s confidence may be improved.If the user can access downloadable resources from the intervention, then the user may generate a deeper understanding of the concepts covered within the intervention.If the users can choose personalizable characters and a variety of modules within the intervention, then this may enable them to maintain stimulation to carry out the task.If the users receive positive reinforcement (reward) from the intervention, then this may motivate them to use the intervention.If the users engage with social scenarios within the intervention, then they may make more appropriate social decisions in the future, which may help enhance social relationships.If the users engage with the intervention, then they may gain a better understanding of their ADHD.If the users engage with the intervention, then improved self-management of their ADHD may improve relationships with friends and family.If the user gains encouragement from friends/relatives to use the intervention, then this could reinforce the user’s engagement with the intervention.If short-term meaningful goals are set for the users via the intervention, then this could encourage them to engage with the intervention.Overall, 7 themes were identified: (1) positive rewarding feedback, (2) downloadable gaming resources, (3) personalizable and adaptable components, (4) psychoeducation component, (5) integration of self-management strategies, (6) goal setting, and (7) context . These themes focused on testing the 9 initial propositions.All participants expressed a wish for immediate positive reward when the user may select a correct response. Of the participants, 1 said that when he or she gets a reward, for example, a sticker at school, it makes him or her feel “proud” (YP5). Examples of instant reward could be auditory confirmation of a correct response and collecting items such as coins, stars, diamonds or trophies. The reward (and the intervention itself) should also be visually attractive:I think that [instant positive reward] will really help his self-confidence.P4Another clinician states the following:I think a lot of the games nowadays build up points and it makes sense...having reward builds up their self-esteem.... And just makes them feel happier.C4In addition, all 21 participants suggested that the instant positive reward component would motivate the user to engage with the intervention. They also felt that additional motivation to engage with the intervention could involve personalizing the reward (n=12), that is, the users can choose their rewards  because of the following reason when referring to CAYP with ADHD:tend to get bored quite quickly.C2A total of 11 participants stated reward could also be given by providing different levels where the use could “level up” or open “new areas” once a previous level is “completed.” Most of the CAYP (n=5) and 2 parents wanted these levels to increase in difficulty:I like harder and harder cos if you do harder and harder you get better and better at it.YP7However, 2 CAYP (YP3 and YP6), 1 parent (P7), and 2 clinicians believed that if levels were too challenging for the users, it could cause frustration and demotivate their engagement with the intervention. Therefore, 1 clinician suggested that there could still be levels and areas to create choice, allowing the users to feel they are progressing, but these levels could have an option to make them easier:...simplify the challenge so you could make the challenges harder...but there could be a simplify option that the kids could use and so the kids that do get frustrated can simplify it and get it done.C1If applicable, the option of using downloadable resources could be made available for when the intervention may not be accessible, for example, if the child/young person has to share a device with siblings, has limited screen time , or is away from home . Participants wanted downloadable resources to have a gaming component, including quizzes, mazes, word searches, crosswords, coloring in, or origami activities .Including quizzes cos I like quizzes.YP1A total of 5 CAYP, 4 parents, and all 6 clinicians requested that the technology should be personalizable and include adaptable avatars, that is, characters they can personalize by changing hair/eye color, gender, clothing, and skin color that can be adapted as and when they wish. Moreover, 4 clinicians believed this was so that the user could “relate” to the intervention and its content:That it’s [the language] not too clinical and that they can actually relate to it... It’s the relating to it really that’s most important. ...you have to be really careful that its not so generalised that they can’t relate to it.C3Moreover, 1 parent (P4), 1 young person (YP4), and 1 clinician (C4) emphasized the importance of having the correct amount of stimulation to ensure the users are not over or under stimulated:You don’t want to over-stimulate them, but you want them to have that draw, I think its finding the right balance between overload and sort of retaining err concentration.P4A total of 5 CAYP, 5 parents, and all 6 clinicians believed it was an important aim for the users to have a good understanding of their ADHD. It was also considered important by 2 clinicians (C2 and C3) that the positive aspects of ADHD should be highlighted through examples of others who have ADHD and have been successful, such as celebrities, as they believed there was a lot of negativity surrounding the condition. Moreover, 1 clinician believed that it could be “life changing” (C1).Another clinician stated the following:Because I want to know about ADHD, what it does and what it effects in your body.YP5Moreover, 1 parent stated the following:Knowledge is power and just giving her the confidence, increased self-esteem.P3A clinician stated the following:I think it could be massive for them across the board it could help them at school, help them learn, help them make friends, help with their relationships with others...C1A total of 5 clinicians wanted interventions for CAYP to self-manage their ADHD to be more positive while not “glossing over” some of the difficulties. All 6 clinicians expanded on the above and stated that when CAYP with ADHD act incorrectly or impulsively, they often feel bad about themselves, and having knowledge about their condition could help prevent this. Overall, 3 CAYP, 4 parents, and 4 clinicians emphasized the importance of understanding the users’ ADHD so the users can explain it to their friends:Cos if I know more I can tell people more about the like what I’ve got [ADHD] so they know what it means.YP4Overall, 5 CAYP, 4 parents, and all 6 clinicians believed an intervention should include strategies to help the children self-manage their ADHD, such as anger management strategies. Moreover, 1 participant stated that he counts to 40 for a total of 3 times to calm down (YP7).Another parent stated the following:He can learn sort of techniques you know sort of self-management techniques trying to calm himself down.P4Another self-management strategy discussed was animated “social scenarios” with alternate endings for the users to choose from to help them understand what acceptable behavior is and is not in social situations. This idea was favored by clinicians (n=5), CAYP with ADHD (n=3), and parents (n=3). Overall, 2 clinicians (C5 and C6) stated this could be beneficial because similar “social stories” are already used with CAYP with ADSD, which is comorbid in many CAYP with ADHD:She seems to learn a lot through like watching videos... if she wants to know how to do something, she goes on YouTube.P1A clinician stated the following:I really like the idea of scenario-based teaching.C2Another clinician said:[Social scenarios] sound like a similar principle to the social stories we use with the children with autism we see. I think that could be useful as it could help the children to reflect on what they might do in a situation before they are in the heat of the moment.C5Overall, 6 parents liked the idea of goal setting within a technological intervention. They liked the idea of short-term goals because of poor working memory in CAYP with ADHD, which means they may find it challenging to process longer-term goals.It was found that the variable context an intervention is delivered in could affect the outcome it may have, and these contexts could be divided into environmental and personal.Overall, 1 parent (P3) and 1 clinician (C5) stated that some CAYP with ADHD also have dyslexia and may struggle to read text; therefore, the background color to any included text should be adaptable. This is because some people with dyslexia find it easier to read text on specific background colors. This could enable the user to access the information more easily. Overall, 1 parent (P1) and all 6 clinicians also believed it is important that the information presented should be developmental and age-appropriate and the language should be suitable to ensure the user can understand the material provided:A whole variety of those different [background] colours then that would make it much more accessible. It would make it easier for them [CAYP with dyslexia as well as ADHD] to read, it could stop the words and the letters moving, it makes it so they can actually read what’s written rather than it being a sea of text they can’t access. There’s a huge overlap between lots of condition like dyspraxia, dyslexia, ADHD, Autism.C5Overall, 13 participants  believed they would be more motivated to engage with a technological intervention if they had encouragement and support from close friends or relatives. Moreover, 1 young person (YP1) stated that her family and her dog could get in the way if she was to use an intervention of this nature, which could affect the effect the outcome intervention has on the user:I think it will be good for them to do on their own but I think it will be good for other people to know what they have looked at so they can reinforce if they have any questions.C3A total of 6 parents believed that supporting their child with an intervention that helps them self-manage their ADHD could help build their relationship with their child.As a result of validating CMOCs with key stakeholders, existing CMOCs have been refined see . All CMOThis study aimed to present an RE approach to develop guidelines that may help the future development of technological interventions, which aim to help CAYP with ADHD self-manage their condition more effectively. A total of 7 key themes emerged from the interviews with key stakeholders: (1) positive rewarding feedback, (2) downloadable gaming resources, (3) personalizable and adaptable components, (4) psychoeducation component, (5) integration of self-management strategies, (6) goal setting, and (7) context . Importance was placed on the variable environmental and personal context in which such an intervention could be delivered; importance was additionally placed on how these contexts could affect the outcomes of the interventions.All participants identified the need for an instant positive reward within a technological intervention for CAYP with ADHD. This is supported by behavior change MRTs such as classical conditioning, which states that unconscious behavior will change when a stimulus is repeatedly paired with a particular response such as rewards . SimilarSome participants  liked the idea of having the option of being able to print off resources that complement the technological intervention in the event that technology is not available . This could be important as CAYP with ADHD are overrepresented in socially deprived areas ,8 and maPrevious evidence suggests that CAYP with ADHD would like a mobile app to be personalizable . It is wParticipants  wanted CAYP to know more about their ADHD so that they could self-manage it more effectively and so that the CAYP could explain what ADHD means to their peers. This concurs with existing literature where emphasis has been placed on the value of psychoeducation for CAYP with ADHD and their families, as an expert understanding of their condition could lead to more positive individual choices ,73. The Overall, 5 CAYP, 4 parents, and all 6 clinicians believed the availability of self-management strategies for ADHD could be useful for CAYP with ADHD. Social learning theory states that individuals can learn by imitating others . AnimateMoreover, 2 clinicians recognized that “social stories” are an effective way to teach CAYP with ASD how to behave appropriately in social situations and are often used in clinical practice ,78. TherFurthermore, “interpreting physiological signs” is also a stream of Bandura’s theory of self-efficacy . This coAs CAYP with ADHD can be impulsive, it was requested that interventions should involve a component to help them when they wish to behave impulsively, for example, when they are angry. Support from this may come from the Social Regulation Theory that states CAYP with ADHD lack self-control, which can affect their working memory . This thOverall, 6 parents liked the idea of short-term goal setting within an intervention. Executive dysfunction theory has been applied to ADHD , and it In accordance with the MRC framework and the International Classification of Function, Disability and Health (ICF), this research found that variable contexts in which an intervention could be delivered could be divided into personal and environmental factors . Figure Moreover, 1 example of an environmental context is support from others. A total of 13 participants believed there was value in CAYP with ADHD having support and encouragement (to use an intervention) from their close friends and families. This concurs with the theory of self-efficacy that states that “feedback and persuasion” from significant others, such as family members, can increase one’s self-efficacy ,80. TherOverall, 1 participant acknowledged that ADHD is a highlight comorbid disorder , which iThis study has highlighted the importance of considering the variable context in which interventions take place . If reseExisting evidence is supportive of a psychoeducation component for such interventions ,73-76; tIn addition, the BCW  providesAlthough a sampling frame was adhered to, ensuring a representative sample of this complex population, the qualitative nature of this research meant that the CMOCs for this study were validated and refined using interview data from a small number of participants (n=21). ADHD is a highly complex neurological condition; therefore, 1 intervention will not suit all CAYP with ADHD, or all families and future technological interventions will need to account for this. In addition, for some, these guidelines and subsequent technology development may still not meet their need for personable one-to-one interaction. Furthermore, this study was limited to the views and opinions of CAYP with ADHD, their parents, and specialist clinicians. Game designers and platform developers were not consulted as it was outside the aims and objectives of this study. Future research may benefit from incorporating the views and opinions of these individuals.Complex interventions for ADHD self-management run the inevitable risk of variable uptake of the intervention among participants ; therefoThis study has adopted the principles of RE  to desig


Objective: Structural and functional abnormalities have been noted in the prefrontal cortex of individuals with neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD). Cortical thickness and gyrification, both of which have been reported as abnormal in the prefrontal cortex in ADHD, are thought to be modulated by genetic influences during neural development. This study aimed to investigate the effects of a polymorphism of the dopamine DRD4 gene (the 7-repeat (7R) “risk” allele) on thickness and gyrification as distinct parameters of prefrontal cortical structure in children with ADHD.Method: Structural images and genetic samples were obtained from 49 children aged 9–15 years (25 with ADHD and 24 matched controls), and measures of cortical thickness and gyrification for inferior, middle, and superior frontal cortex were calculated.Results: A significant interaction between diagnosis and genotype on prefrontal gyrification was observed, largely driven by reduced inferior frontal gyrification in patients who carried the DRD4 7R allele. Furthermore, inferior frontal gyrification—but not thickness—related to everyday executive functioning in 7R allele carriers across groups.Conclusions: Prefrontal gyrification is reduced in children with ADHD who also carry the DRD4 7R allele, and it relates to critical functional skills in the executive domain in carriers of the risk allele. More broadly, these effects highlight the importance of considering precise neurodevelopmental mechanisms through which risk alleles influence cortical neurogenesis and migration. Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous neuropsychiatric disorder characterized by developmentally inappropriate symptoms of inattention, impulsivity, and hyperactivity. The disorder is thought to affect around 1–5% of children and is highly heritable, with multiple genes of small effect contributing to the clinical phenotype , 3] haveA bulk of the genetic polymorphisms identified to be associated with ADHD in genome-wide studies is functionally related to neural development . Animal A large genetic imaging study seeking to identify the mediating effect of neuroanatomical deficits in the relationship between the DRD4 7R risk allele and ADHD phenotype revealed lateral prefrontal thinning in patients with ADHD . The obsDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) clinical diagnosis of ADHD (combined subtype) and an established positive response to methlyphenidate (MPH) were recruited from child psychiatry and community pediatric clinics in Nottinghamshire and Lincolnshire. Controls were recruited from primary and secondary schools in the Nottinghamshire region and matched for age ( ±6 months), sex, and socioeconomic status. Exclusion criteria included presence or history of head injury, psychosis, epilepsy, Tourette syndrome, autistic spectrum disorder, moderate or severe learning difficulties, or current use of non-stimulant or other psychotrophic medication (except melatonin). After a complete description of the study, written informed consent and verbal assent were obtained from parents and children, respectively. The study was approved by local Regional Ethics Committee and the Research and Development Departments of Nottinghamshire Healthcare NHS Trust and Lincolnshire Partnership NHS Foundation Trust.Participants were recruited as part of an functional magnetic resonance imaging(fMRI)/electroencephalography (EEG) study reported elsewhere , 35 and Neuroimaging data from 54 children were available. A quality control inspection assessed images for gross structural abnormalities, motion, and other artifacts. Data from five subjects  were not included because of motion artifacts. In the final sample, we report data from 49 subjects with good quality neuroimaging and genotyping data; 25 subjects with ADHD  and 24 healthy controls (12.93 ± 1.62 years).T scores  are used to interpret the child’s executive functioning, with high scores indicating potential problems.Neuropsychological measures including IQ and reading ability were obtained from all participants as part of a testing battery see Table 1.T1-weighted (T1W) brain images in the sagittal plane were obtained with a Philips Achieva 1.5-T MRI scanner with an eight-channel SENSE head coil using a 3D turbo field echo (TFE) sequence with the following parameters: 160 contiguous slices; TR/TE, 9.9/3.7 ms; matrix size, 256 × 256; voxel size, 1 × 1 × 1 mm. Head movement was minimized by the use of foam pads placed within the head coil.http://surfer.nmr.mgh.harvard.edu/. Briefly, following skull-stripping and intensity correction, the gray–white matter (GM/WM) boundary for each cortical hemisphere was determined using tissue intensity and neighborhood constraints. The resulting surface boundary was tessellated to generate multiple vertices across the whole brain before inflating. Using a deformable surface algorithm guided by the gray–cerebrospinal fluid (CSF) intensity gradient, the resulting gray–white interface was expanded to create the pial surface. The inflated surface was then morphed into a sphere, followed by registration to an average spherical surface for optimal sulcogyral alignment. The neuroanatomical parcellations were obtained using the Destrieux sulcogyral based atlas, which follows the anatomical conventions of Duvernoy  and summed up to obtain the total cortical surface area. Cortical thickness was measured using the method described by Fischl and Dale   using imSamples for genotyping were collected from participants using an Isohelix buccal swab (Web Scientific) or a mouthwash solution  depending on subject preference. Samples were always collected following an abstinence from food and drink of at least 1 h.DNA was extracted by centrifugation; 3,000 rpm for 10 min at 4°C. Pellets were resuspended in 500 µl of 10 mM NaCl/10 mM ethylenediaminetetraacetic acid (EDTA) and vortex mixed prior to centrifugation at full speed for 1 min. Pellets were resuspended in 500 µl of 50 mM NaOH, vortex mixed, and incubated at 100°C for 10 min. After centrifugation, 100 ml of 1 M Tris (pH 7.5) was added and vortex mixed. A 1:5 dilution of this stock was made and used in the PCRs.The number of 48-bp repeats in each participant was determined using PCR across the repeat region. Primers and PCR conditions were as described by Nanko et al. , except t tests for continuous variables or chi-square (χ2) tests for categorical variables between patients and controls (CTRL) as well as between DRD4 7R carriers and non-carriers. A significance level of p < 0.05 was used for all tests.All statistical analyses were conducted using SPSS v.25 (IBM Inc). Demographic and clinical characteristics were compared using two-tailed p values for any follow-up tests were calculated from bootstrapped 95% confidence intervals for the parameter estimates . Where the assumption of sphericity was violated, degrees of freedom were adjusted using the Huynh–Feldt correction.Prefrontal gyrification was analyzed using a repeated-measures analysis of covariance (ANCOVA) with HEMISPHERE  and REGION  as within-subject factors, DIAGNOSIS (ADHD vs. CTRL) and GENOTYPE . There was also a significant DIAGNOSIS × GENOTYPE × REGION effect, F = 6.017, p = 0.014.p = 0.042 for interaction parameter). Results from each region in turn indicated that this interaction was largely driven by a significant interaction effect in inferior frontal cortex (p = 0.019 for the interaction parameter). These data are shown graphically in As the assumption of homogeneity of variance and normality of residuals was violated in these models, we tested these interactions further using a series of bootstrapped univariate factorial ANCOVAs, first with global mean frontal LGI as the dependent variable, and then, to test the three-way interaction, with mean LGI in each frontal region  in turn as the dependent variable. For the DIAGNOSIS × GENOTYPE interaction, the effect remained significant  = 5.031, p = 0.04 , with no significant effect for the global covariate, F = 3.28, p = 0.09. There was a significant DIAGNOSIS × REGION effect, F = 5.43, p = 0.027. As the variances for the inferior frontal LGI were not equal between the two groups, we used Kruskal–Wallis H test to confirm a significant effect of diagnosis on inferior frontal LGI  among carriers.An analysis of simple main effects  revealed that the observed effects on gyrification were driven by a significant difference in the risk carriers, with children with ADHD showing a significant reduction in prefrontal gyrification, F = 2.28, p = 0.10 , but a significant effect for the global covariate, F = 14.1, p = 0.001. There was no significant DIAGNOSIS × REGION effect among non-carriers, F = 2.29, p = 0.14. As the residuals for the inferior frontal region were not normally distributed, we used Kruskal–Wallis H test to confirm the lack of a significant effect of diagnosis on inferior frontal LGI  among non-carriers.In non-carriers, there was no significant diagnostic effect, F = 4.1, p = 0.06] and children with ADHD . Kruskal–Wallis H test was not significant among both control subjects  and children with ADHD .We also noted that there was no significant effect of genotype among both controls  and well-matched controls, some limitations must nonetheless be acknowledged. While the sample size is similar to or larger than that of many other morphometry studies . This work was supported by a grant from the Wellcome Trust (grant number: 076448/Z/05/Z) to CH .LP reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Janssen Canada, Otsuka Canada and Sunovion outside the submitted work.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


HSPG2 have recently been reported to function as a potential contributor to the susceptibility of adolescent idiopathic scoliosis (AIS) in the Caucasians. A replication study in the different population is warranted to validate the role of HSPG2 in AIS. The aim of this study was to determine the association between HSPG2 and AIS in the Chinese patients and to further investigate its influence on the phenotype of the patients.Rare variants of HSPG2 was genotyped in 1752 patients and 1584 normal controls using multiple ligase detection reactions. The mRNA expression of HSPG2 in the paraspinal muscles was quantified for 90 patients and 26 controls. The The Student’s t test was used to analyze the inter-group comparison of the HSPG2 expression. The relationship between the HSPG2 expression and the curve magnitude of the patients was analyzed by the Pearson correlation analysis.SNVs p.Asn786Ser of HSPG2 was found in our cohort. The mRNA expression of HSPG2 in patients was comparable with that in the controls . 42 patients with curve magnitude > 60 degrees were assigned to the severe curve group. The other 58 patients were assigned to the moderate curve group. These two groups were found to have comparable HSPG2 expression . And there was no remarkable correlation between the expression level of HSPG2 and the curve severity .No case of mutation in the reported SNV p.Asn786Ser of HSPG2 gene was not associated with the susceptibility or the phenotypes of AIS in the Chinese population. The whole HSPG2 gene can be sequenced in more AIS patients to identify potentially causative mutations. Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity that affects millions of children worldwide . To beneConfined by the low efficiency to define the genetic markers, whole-genome linkage analysis was firstly used in the genetic research of AIS which could only identify large chromosome regions potentially containing disease-related genes , 11. GraTo overcome the above-mentioned limitations of candidate genetic association studies, a much powerful tool, genome-wide genotyping chip, was utilized to identify the susceptible gene of AIS –26. SharWith the advances of sequencing techniques, more research teams have begun to analyze the role of rare variants in AIS using whole exome sequencing (WES) in recent years –29. WithHSPG2 were reported to function as a potential contributor to the susceptibility of AIS in the Caucasians [HSPG2 in AIS. This study aimed to determine the association between HSPG2 and AIS in the Chinese patients and to further investigate its influence on the phenotype of the patients.In a recent study, rare variants of ucasians . ObviousUnder the approval of the local institutional review board, a cohort of 1752 female AIS patients and 1584 controls were included in the current study. All the patients were excluded to have neurological defect through MRI examination. All the controls were excluded to have scoliosis through Adam’s Forward Bend Test using the standard criteria performed by a senior spine surgeon (Z.Z.). Demographic data were collected for each participant, including initial age, curve pattern and curve magnitude measured by the Cobb angle method on the standing posteroanterior X-ray films.HSPG2 was genotyped for all participants. Allelic-specific multiple ligase detection reactions (LDR) was used for genotyping assay as previously reported, with the primer shown in Table All the subjects signed the informed consent for the collection of blood samples. Genomic DNA was then extracted with the commercial kit . Single nucleotide variant (SNV) p.Asn786Ser rs143736974) of 43736974 HSPG2 gene were identified through the Ensemble database (http://www.ensembl.org/index.html). GWAS database that was composed of 1446 AIS patients and 2080 controls was processed with the PLINK  to determine the genotyping results of these common variants.Common variants covering HSPG2. Twenty-eight female lumbar disc herniation (LDH) patients with no presence of spinal deformity were included as the controls. The paraspinal muscle was collected from each subject during the surgery. For AIS patients, we collected the muscle sample from both the concave side and convex side at the apex of the curve. Total RNA was then extracted from the muscle tissue using a commercial kit (CWBio. Co. Ltd). The mRNA expression of HSPG2 was quantified with real-time polymerase chain reaction (PCR) on ABI 7900HT, with GAPDH used as the endogenous control. All amplifications were performed in triplicate. The relative expression of HSPG2 was normalized using the ΔΔCt method. The primers of HSPG2 and GAPDH were shown in Table Ninety-eight female AIS patients were included in the expression analysis of HSPG2. The relationship between the HSPG2 expression and the curve magnitude of the patients was analyzed by the Pearson correlation analysis. The statistical was set at p < 0.05.SPSS version 17.0  was used for data analysis. Cochran-Armitage trend test was used to calculate the association between common variants and AIS. Patients included expression analysis were classified into different subgroups according to the curve pattern or the curve severity. The Student’s t test was used to analyze the inter-group comparison of the baseline characteristics and mRNA expression of The mean age of patients included in the LDR analysis was 15.3 ± 3.4 years (range 10.5–18.8 years). The mean curve magnitude was 54.3 ± 11.2 degrees (range 27–72 degrees). One thousand eighteen patients had curve magnitude more than 50 degrees and thus underwent posterior spinal correction surgery. The mean age of the healthy controls was 18.9 ± 3.2 years (range 16.5–22.8 years).HSPG2 was found in our cohort. All the 3336 subjects were found to have genotype TT. A total of 16 SNPs covering HSPG2 were analyzed, with the distribution of minor allele frequency summarized in Table No case of mutation in the reported SNV p.Asn786Ser of HSPG2 was successfully detected in the paraspinal muscles of 90 patients and 26 controls. There was no significant difference regarding the mean age of the two groups . The mRNA expression of HSPG2 in patients was comparable with that in the controls .A total of 98 patients and 28 controls were included for expression analysis. Eight patients and 2 controls were excluded from the analysis due to degradation of total RNA. The expression level of HSPG2 expression . And there was no remarkable correlation between the expression level of HSPG2 and the curve severity , either.For the 90 patients included in the expression analysis, 42 patients had curve magnitude more than 60 degrees, thus assigned to the severe curve group. Forty-eight patients with curve magnitude less than 60 degrees were assigned to the moderate curve group. These two groups classified by curve severity were found to have comparable HSPG2 expression between the curve pattern groups .As for the curve pattern, 67 patients had single thoracic curve and the other 23 patients had double major curve. There was no significant difference of p value of less than 5.0 × 10− 8. Obviously, a large sample size and a rigorous setting of statistical power are key factors to ensure reliable and reproducible findings in genetic studies.Genetic findings of AIS have been greatly hindered by its clinical and genetic heterogeneity. Previous association studies have revealed many disease-related genes, most of which however appeared inconclusive as indicated by the following replication studies , 32, 33.HSPG2 gene as a novel causative variant of IS. Enrichment of this mutation was then validated in two independent cohorts composed of 241 IS patients [HSPG2 with the development of AIS, we performed the genotyping of p.Asn786Ser in a large cohort consisted of 1752 patients and 1584 controls. No case of mutation was found in this cohort as all the subjects presented the same genotype TT. As for common variants covering HSPG2, none of the 16 SNPs had remarkably different allele frequency between the patients and the controls. Moreover, we observed comparable HSPG2 expression in the paraspinal muscles between the patients and the controls. To summarize, our findings did not support the association of HSPG2 with the susceptibility of AIS in Chinese population.Another difficulty of AIS genetic research lies in that the reported common variants can only explain a small amount of AIS heritability. All the susceptible variants reported by previous GWASs of AIS had an OR value between 1 and 2, leaving over 90% of the AIS heritability unexplained –26. Sincpatients . To valiHSPG2 gene, which has 94 exons, encodes perlecan which binds to basement membrane proteins such as collagen and laminin and to cell surface receptors [HSPG2 mutations could lead to a more severe phenotype in human disease, such as Schwartz- Jampel syndrome Type 1 and Dyssegmental Dysplasia, Silverman-Handmaker Type [HSPG2 may be associated with a progressive IS and acted as a potential contributor to the phenotype. Aiming to clarify the relationship between HSPG2 and phenotypes of the patients, we classified patients into different subgroups according to the curve pattern or the curve severity. We found that HSPG2 expression was not associated with either the curve severity or the curve pattern. Herein, it appeared that HSPG2 had no effect on the phenotype of the AIS patients.eceptors . Homozygker Type , 38. Schker Type . Baschalker Type  thereforHSPG2 in the development of AIS still needs further investigation. The primary limitation of our study lies in that we did not sequence all the exons of HSPG2. It cannot be excluded that enrichment of other mutations of HSPG2 could play a role in AIS. Besides, the function of p.Asn786Ser should be investigated through in-vivo cellular experiment to clarify its role in AIS.It is unlikely for the current study to have false-negative results as our sample size is large enough to detect the potential mutation. The susceptibility genes of AIS may play important roles in the diagnosis and therapy of AIS in the future. We believe that the role of HSPG2 gene was not associated with the susceptibility or the phenotypes of AIS in the Chinese population. In future study, functional studies of p.Asn786Ser is warranted to clarify whether this variant can regulate the expression of HSPG2. The whole HSPG2 gene can be sequenced in more AIS patients to identify potentially causative mutations.


The utilisation of rehabilitation resources was higher in the ADHD group than in the non-ADHD group. The number of school-aged children with ADHD was higher than the number of preschool-aged children (p < 0.001). The highest utilisation of rehabilitation resources was observed in clinics (p < 0.001). In terms of region, Taipei exhibited the highest utilisation of rehabilitation resources, and the East exhibited the lowest resource utilisation (p < 0.001). Prediction of the use of rehabilitation resources, average cost, average frequency of visits, and total annual cost was affected by factors such as the average frequency of rehabilitation use, demographic characteristics, and the hospital characteristics and location (p < 0.001). The number of children with ADHD and rehabilitation use are increasing yearly; however, limitations in payment restrict the growth of rehabilitation resource use in hospitals. Supplementation of rehabilitation resources at clinics accounts for more than 60%, however, the total annual cost is less than what is observed for hospitals (p < 0.001). Policies should be established to aid in the early detection and treatment of children with ADHD to improve treatment outcomes and reduce the family burden and treatment expenditure in the future.Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children. This study investigated the use of rehabilitation treatment in Taiwan. We selected children aged 3–12 years from the National Health Insurance Research Database from 2008 to 2012 and included them in the analysis. The children who received a diagnosis according to the International Classification of Diseases, Ninth Revision, Clinical Modification were divided into two groups: ADHD and non-ADHD. We used the chi-squared test, independent sample  Attention-deficit hyperactivity disorder (ADHD) is one of the most common mental and neurodevelopmental disorders in children. Children with ADHD exhibit numerous associated symptoms and impairments in development, socialisation, emotional and cognitive functioning, as well as behaviour problems . ADHD haPreschoolers with ADHD incurred 17.6 times higher average costs per annum than preschoolers without ADHD. A study reported an average cost of £562 for those with ADHD compared with £30 for controls . PreschoPage et al.  suggesteIn 2002, the first study on the use of health care costs of ADHD in Germany was conducted, reporting an average annual cost of €142 million. These values are considerably lower than the values calculated in the United States . AnotherThere is very limited information on nonpharmacological and multimodal management for adjuvant therapy and medical costs among patients with ADHD in Taiwan. Only one cross-sectional study according to the Taiwan National Health Insurance (NHI) claims database was conducted among children with ADHD aged 0–7 years in outpatient rehabilitation care in 2009. The results showed that children with ADHD aged 6–7 years tended to incur less medical costs including rehabilitation fees and comorbidity medical fees than those aged 0–2 years . Due to Data from the NHI claims database from 2008 to 2012 were analysed. These data included sex, date of birth, health insurance identity, medical care setting, location, average outpatient care expenditure, number of outpatient rehabilitation visits (number of patient times outpatient frequency), annual outpatient care cost , and discharge diagnosis of disease according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding system. Symptoms of ADHD usually occur around the age of 3. The general diagnosis age is in kindergarten or elementary school . Adolesc2) was used to compare demographic and medical care setting characteristics and rehabilitation care expenditures in the ADHD and non-ADHD groups. The t test was used for evaluating outpatient care expenditure, number of outpatient rehabilitation visits, and annual outpatient care cost in children with ADHD. A generalized linear model was used to evaluate the associated factors of rehabilitation care expenditure and a negative binomial regression was conducted to estimate the number of visits in children with ADHD.Data were analysed using STATA 12.0 . The chi-squared test (χp < 0.001), with a male: female ratio of approximately 3:1. The average age of rehabilitation resource use was 6.38 years. In the ADHD group, the proportion of school-age children was 1.9 times higher than that of the preschool-age children (p < 0.001) by using chi-squared test. The distribution of rehabilitation use in the ADHD group was higher than in the non-ADHD group (p < 0.001). Eighteen percent and 1.6% of children with ADHD had a disability card and catastrophic illness card, respectively. All of the differences were significantly different (p < 0.001).p < 0.001).p < 0.001). Most of these settings were non-teaching hospitals , and these cases were mostly located in northern Taiwan .p < 0.001).ADHD has the potential to be a lifelong problem, particularly if untreated, and the burden of social costs and excessive care expenditure is significant . HoweverIn this study, the number of diagnoses from 2008 to 2011, irrespective of the number of people who used rehabilitation resources or were diagnosed as having ADHD, exhibited a yearly increase. Although the number of people who used rehabilitation resources in 2012 was the lowest in the past 5 years, the highest number of people diagnosed as having ADHD and the highest average cost of rehabilitation resource use were observed in 2012.p < 0.05). Therefore, male sex can be used as a predictor for the subsequent use of rehabilitation resources. The exact cause of this difference remains unclear. Boys may be predominantly more hyperactive and may exhibit more externalizing symptoms, thereby resulting in a higher referral rate.The male: female ratio was 3:1, similar to that in other studies . IrrespeIn this study, an annual total cost of 17,985 points  per person was observed, exceeding the average annual outpatient expenditure of 12,000 points per person obtained from Taiwan NHI from 2003 to 2006 . Howeverp < 0.05). However, the overall cost of rehabilitation for the total annual cost, average cost, average number of visits, was lower in the school-age group than in the preschool-age group. This may be because students in the lower grades of elementary school have a half-day of school and thus have more time to participate in rehabilitation training programmes. The majority of the parents of children with the first diagnosis of ADHD at school age were willing to accept nondrug treatment options to ameliorate their children’s symptoms. Although the proportion of rehabilitation resource use after school age was higher, the children’s heavy workload, full school days, and lack of persistence may have been what led parents to prefer the use of medicines to nonpharmacological treatment, potentially resulting in the decline in the overall rehabilitation costs and the number of visits in school-age group. Moreover, because rehabilitation treatment fees are higher for preschool-aged children, the use of rehabilitation resources and the total annual cost, average cost, and average number of visits were higher in the preschool-age group.In this study, the average age of ADHD diagnosis was 6.38 years old, and the average ages of preschool and school children were 4.14 and 7.88 years, respectively, which is consistent with the average school age of American children, reported as 7.3 years . In thisp < 0.05). Children with the catastrophic illness card can be exempted from medical costs, and those with the disability card can apply for more service supplements (such as reimbursement for transportation fees). The catastrophic illness card and disability card had more physical conditions, potentially leading to more frequent rehabilitation therapy and medical treatment and thereby increasing the cost, the number of visits, and consumption of medical resources.In the linear regression, the total annual cost, average cost, and average number of visits were significantly related to the children having a catastrophic illness card and disability card (p < 0.05), which can be explained by the higher supplementation of resources by clinics.In terms of hospital characteristics, most rehabilitation resources were provided at primary clinics, accounting for more than 60%, followed by metropolitan hospitals, medical centres, and local community hospitals. The demand for rehabilitation resources was presumed to be increasing in clinics, which accounted for more than half of the rehabilitation resource settings because of the increase in hospital demand. Moreover, non-teaching hospitals provided more rehabilitation resources than teaching hospitals (p < 0.001). The prediction of rehabilitation resource use for ADHD, the average cost, the average frequency, and the total annual cost were affected by factors such as diagnosis, the year of rehabilitation use, demographic characteristics, and hospital characteristics and location (p < 0.001).The average cost per year, frequency of visits, and annual total cost were higher in the ADHD group than in the non-ADHD group  of ADHD rehabilitation therapy referrals were obtained from rehabilitation physicians and only 7% from child psychiatrists ; therefoSecond, one declaration of outpatient rehabilitation service containing six different dates of treatment cannot represent the intensity and persistence of treatment. Some hospitals provide the therapy at the patients’ own expense, which could not be considered in this study.Third, the information used in this study represents a secondary data analysis of the health care database maintained by the National Institutes of Health. The database lacks information on the social status of parents, family income, educational background, quality of family interaction, willingness to seek treatment, or restrictions on their own expenses.Studies on the use of nonpharmacological treatments as rehabilitation resources in Taiwan are limited. Therefore, further investigation on this topic is warranted. Currently, the number of people who use rehabilitation resources is increasing, however due to the total payment limitation, rehabilitation resource provision has become saturated which limits the growth of rehabilitation resource use in hospitals. Rehabilitation treatment requires more professional staff and more time. Due to the total payments for hospitals, it causes a reduction in the supply of rehabilitation and human resources. The value of manpower is not equal to the general payment provided by the NHI. A seriously uneven distribution of medical resources is observed in Taiwan, with the least medical resources being available in the East and the most being available in the North. Access to medical resources in remote areas remains a serious problem. The payment for clinics is less than half of that for medical centres and regional hospitals. Though the most supplement of rehabilitation resources is provided by clinics (60%) but the average annual cost is less than hospitals. This disparity reduces willingness to provide health care service supplementation from clinics. The inadequacy of rehabilitation resources critically restricts the treatment opportunities for children.ADHD involves not only medical costs but also educational and social costs. Sufficient medical resources must be available to families to aid parents in caring for their children with ADHD and address medical and educational problems. To invest more resources in social costs, the government must develop an effective advanced policy to improve the current situation by providing sufficient assistance to children and their families to reduce future burdens on families, education, and society.


Teachers’ misconception on Attention Deficit/Hyperactivity Disorder (ADHD) in general and the implementation of effective educational strategies for children with this problem in particular is one obstacle that largely impacts the academic and overall success of school children with this problem. In Ethiopia, despite there are thousands of school children with this ADHD, no studies have been conducted to examine school teachers’ understanding about problem. This research was therefore aimed to investigate primary school teachers’ misconceptions about ADHD in Western Ethiopia.In this study, 76.2% of respondents had misconception on general awareness of ADHD. More than half (62.7%) of them had misconceptions on the diagnosis and on 81% had misconceptions regarding treatment of the problem. Concerning teachers’ misconception on the contemporarily recommended educational placement of students with ADHD, 141 (68.3%) have said that such students should be placed in part time special education. The findings of this research have clearly indicated that primary school teachers have a wide range of misconceptions about the ADHD. It also reflects the need of equipping teachers with basic knowledge of ADHD which also enables them provide effective support for students with this exceptionality. Attention Deficit/Hyperactivity Disorder is one of the frequently diagnosed psychiatric problems in childhood. The American Psychiatric Association estimated the prevalence rate of ADHD to be 3–7% among school-age children . Also, AFamiliarity of Attention Deficit/Hyperactivity Disorder can amplify teachers’ self-belief in teaching and supervising children with ADHD , 5. HencTeachers who have good understanding about ADHD are most often better prepared to be in a position to offer adequate teaching assistance and render required support for children with ADHD. Moreover, teachers’ misconception on the implementation of effective educational strategies such as appropriate educational placement of such students is one obstacle that largely impacts the academic and overall success of this special population. It was also found that teachers have acknowledged that they have probably no or little opportunity of additional training related to ADHD. As a result, almost all teachers across many countries are distressingly unnamable at least to recognize a child with ADHD and poorly involved in its diagnosis and treatment process –16, 26.In Ethiopia, despite thousands of school children suffer this problem, only a small number of studies have been conducted to examine school teachers’ misconception about this health problem. This research was therefore aimed to investigate primary school teachers’ misconceptions about ADHD in Western Ethiopia.This study was undertaken in 10 government and 20 private primary schools in located in Nekemte town. Nekemte, the capital city of East Wollega zone is found 331 km away from the capital Addis Ababa to the West.School based descriptive cross-sectional study design was undertaken. All primary school teachers in the selected schools and those who fulfilled the inclusion criteria were involved. Non probablity conviniance sampling technique was used to recruit the study participants. The the study was undertaken from December 2016 to January 2017.The tool used to undertake this research was adopted from previously conducted a research which is also standard questionnaire known as Attention Deficit Disorders Scale (KADDS) .After data collection, each questionnaire was checked for completeness before data entry. Data was analysed using SPSS version 20. Frequency tables, graphs and descriptive summaries were used to present the key findings of the study. Binary logistic regression was done to see the existing associations between dependent and independent variables.In this study, 234 of total respondents were selected and responded to the provided questionnaires. As about 28 of the distributed questionnaires were incomplete, questionnaires from 206 participants were analyzed making the response rate of 88.03%.Regarding the key socio demographic characteristics of the study participants, about half (50.5%) were female. Concerning their age, about 62.6% of them were above 40 years old. On the other hand, around 42% of the study participants had more than 16 year of teaching experience. As to their maximum completed level of education, more than half (60.7%) of the selected teachers were first degree holders.In this study, respondents’ misconception of ADHD in terms of general awareness, diagnosis, and treatment of the disorder. As revealed in this research, the vast majority (76.2%) of teachers who participated in the study were found to have misconception about Attention Deficit Hyperactivity Disorder.Regarding questions asked to assess how to diagnose a child with ADHD, more than half (55.3%) of the teachers have responded correctly. While around 11.2% of the study participants had misconceptions on the diagnosis of the problem, significant proportion (33.5%) of them did not respond to the provided questions (lacks). Similarly, out of all respondents, 81% of them had misconceptions on treatment of a child with ADHD  teachers said the students should be placed into part time special education, 22 (10.7%) and 35 (17.2%), respectively recommend full time general education and full time special education. The remaining 8 (3.8%) of the study participants said that they had not known the current recommendation.Binary logistic analysis was done between the teachers’ sources of information and separately having general awareness of ADHD as well as with how to diagnose the problem and statistical significance was considered at P < 0.05. Similarly, logistic analysis was done between sources of information on ADHD and misconceptions related to the most appropriate educational placement Tables  and 2.TaTeachers play a major role both before and after the child was diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD). During pre-diagnostic period, teachers are the closest and familiar person, apart from family members, who can report crucial information about a child’s in-class behavior and refer him to be evaluated and diagnosed. Following the diagnosis, teachers are expected to help in managing ADHD pupils by adjusting classroom environment and delivering cognitive-behavioral therapy to promote self-control . The resGenerally, out of all respondents, 76.2% were found to have misconception on general awareness of ADHD. This is in line with findings study done in Egypt which found that 76.1% respondents in similar study had misconceptions on basic awareness of the problem . SimilarThe third wing in assessing the misconception and/or knowledge level of the school teachers in this study was on treatment of ADHD. With this regard, responses on treatment of ADHD revealed that 81% of the teachers have a misconception. Only 19% were aware that there is no evidence of the effectiveness of the mentioned type of treatment for children with ADHD. Regarding this the highest proportion of incorrect responses  was on item 39: “Children with ADHD generally display an inflexible adherence to specific routines or rituals”. Less than 10% of the teachers in our survey thought mistakenly that children with ADHD have an inflexible adherence but special education given to these children’s change their obedience. These particular findings are consistent with the findings of previous studies done by Canu and Mancil, Ghanizadeh et al. and few more authors of similar studies –24.Teachers who are knowledgeable about ADHD are better prepared to be in a position to offer adequate teaching assistance and support children with ADHD –27. TeacPrevious researches indicated that there is a predominantly negative attitude in children towards their peers and that impairment in peer relations known to be common in children with ADHD. Therefore, the contemporary advice is that it is extremely important to build a classroom community where all students and students with characteristics of ADHD specifically, feel safe and included . ConcernIn general, the results of this research clearly indicated that the teachers who participated in this study had a wide range of misconceptions about the ADHD. The results from this study also brought light to the need that teachers themselves should be educated and supported in regarding ADHD through in-service training which ultimately enables the teachers implement effective support for school children with this exceptionality.As this study was done only on primary school level the research did not know the possible some other misconceptions of teachers at secondary school level. Also, the study did not consider teachers’ misconception of ADHD in rural schools which could be the worst due to variation in information access.


Zea mays subsp. mays Rostrata Group and its current distribution were reconstructed. It emerged that beaked maize originated in the study area and it is one of the oldest genepools available not subjected to formal crop improvement. We identified 28 landraces of beaked maize currently cultivated, 18 here recorded for the first time. The cultivation of more than half of the 28 landraces has continued throughout the last 80 years in a few fragmented localities that can be regarded as “refugia”. The survival of these landraces from substitution with high-yielding cultivars and unidirectional introgression has been mainly due to active on-farm conservation performed by custodian farmers and secondarily to cultivation in isolated areas . After decades of genetic erosion, beaked maize has since the late 1990s experienced a revival, in terms of an increasing number of cultivation localities and the level of product commercialization. This process is mostly spontaneous and only occasionally mediated by governmental institutions; it is linked to the rediscovery of local food products, in this case mainly polenta, a dish made of corn flour, which used to be the staple food across northern Italy. The ex situ conservation of beaked maize and on-farm measures put in place by the farmers to prevent introgression are also assessed. Further research and collecting missions are needed to provide an inventory of open-pollinated landraces of other landrace groups that have survived genetic erosion in Europe. To meet this aim, extensive ethnobotanical surveys, such as the one performed here, are very powerful tools in detecting these genetic resources.Crop landraces are fundamental resources to increase the eroded genepool of modern crops in order to adapt agriculture to future challenges; plus, they are of immeasurable heritage and cultural value. Between the 1940s and the 1960s open-pollinated varieties (OPVs) of flint and semi-flint maize in Europe were almost completely replaced by high-yielding hybrid dent cultivars selected in North America. No comprehensive assessment was performed after the 1950s to understand which maize genetic resources survived genetic erosion in northern Italy, an area characterized by a high degree of landraces extinction and introgression, intensive hybrid dent monocultures, as well as being one of the hotspots of maize cultivation at a continental level. Among these landraces, beaked maize represents a peculiar case study for assessing the survival of OPVs in intensive cropping systems. By means of ethnobotanical and literature surveys, the history of  Crop genetic diversity is an indispensable resource for farmers and breeders to select new crop cultivars . The bulin situ and ex situ conservation measures, must be put in place  cultivation in Europe appears to be as a very suitable model for the study of all the aforementioned phenomena of agrobiodiversity loss, conservation and revival. Europe is the third largest maize producer and consumer worldwide . This assemblage of landraces, whose history has never been unambiguously clarified, was thought to have originated in northern Italy and for a period was preferred by farmers to other flint landraces for the production of polenta. It belongs to an early generation of local open-pollinated landraces that preceded the introduction of the improved Italian cultivars in the 1920s–1930s and the United States’ dent hybrids in the late 1940s  and present (post-1990s) times. These, together with the municipalities where the cultivation of beaked maize persists today, are highlighted in Northern Italy consists of eight administrative regions  and 46 provinces covering an area of more than 120,000 square kilometres. This geographic area is characterized by wide alluvial plains, the Po and the Venetian Plains, enclosed by two main mountain ranges, the European Alps in the north and in the west and the Apennines in the south. The plain areas, thanks to the abundance of water, are particularly suited to large, industrial monocultures of maize and rice. Northern Italy is indeed a leading producer of the latter two cereals at a European level , with thDespite well-known genetic erosion, introgression events and substitution of landraces with “improved cultivars” recorded in the study area in a multitude of crop genepools, such as apple see , maize  and riceThe present study is based on ethnobotanical surveys conducted by the authors across northern Italy . We locaInformation from interviews was integrated with data acquired from the investigation of all the available historical and contemporary agronomic, botanical and culinary literature sources .The names of taxa (from family to variety ranks) and the names of culta  are treated according to the rules of the International Code of Nomenclature for algae, fungi, and plants ICN,  and the Morphological characteristics were designated by means of botanical terminology in the description of the Rostrata Group, whereas the related agronomical terms  of Bergamo, Istituto Strampelli of Lonigo germplasm bank, University of Pavia Germplasm Bank, Svalbard Global Seed Vault and Trentino Seed Bank of MUSE—Museo delle Scienze di Trento, Trento ; (c) Ark of Taste: Slow Food online catalogue of the quality food products at risk of extinction (https://www.fondazioneslowfood.com/en/); (d) De.Co.: acronym for “Denominazioni Comunali” , is a guarantee label assigned by Italian municipalities to food and agricultural products from their own territory, in compliance with Law 8 June 1990, n. 142.Based on information collected through ethnological and literature surveys we assessed the “revival” of the landraces. A landrace was considered revived when at least one of the following criteria was met: (1) its cultivation was resumed or increased in terms of the number of localities of cultivation in the last 20 years; (2) products derived from the landrace that have started to be commercialized to the public in the last 20 years; (3) occurrence of the following protection and promoting measures applied to the landrace itself or its products see also : (a) NatSimilarly to other maize landraces “discovered” during the early 20th century in Italy  rostrata Bonaf.  a cultivated specimen of maize, present since 1837 in the aforementioned garden, not previously mentioned in his monumental monograph on this crop  of the ICN; the correct name at species level was published by Zea mucronata Poit.). In the same years, Rother spitzkörniger Mays” (with dark-red and pointed to muticous kernels) obtained from the Berlin Botanical Garden, while The earliest reference to a maize with beaked kernels in Europe dates back to Matthieu Bonafous in , directohis crop . It was his crop . On the formentone rostrato di Lombardia”  (Z. mays var. rostrata within the popcorns (Z. everta Sturtev.), probably on the basis of its morphological affinity, communicated by Brown to Formentone uncinato, a becco”  and “Zea m. rostrata”, plants taller (>2 m) and with a longer maturing cycle than previous descriptions. Similarly, two illustrations of the “Maïs jaune à bec” published in France by In Italy, as hoped by Bonafous in , beaked bardia”) , subsequbardia”) , probablbardia”) , the probardia”)  and Bellbardia”) , mostly bardia”) . SturtevProbi contadini”) in Comun Nuovo  type, a category comprising cultivars and landraces that needed to be sown between the second half of April and the middle of May. Based on the examination of both morphological and phenological characteristics of the accessions acquired during the Italian maize germplasm collecting mission promoted in 1954 by the Stazione Sperimentale di Maiscoltura (now CREA-MAC) of Bergamo, Rostrato” agroecotype, a member of the racial complex “Insubrian flints and semi-flints” or “Padani”.Considering the late maturity cycle, Although the subject of experimental mass selection, and inter- and intravarietal crosses for more than a decade, which resulted in the constitution of the formally improved yet unsuccessful cultivar ‘Rostrato Cajo Duilio’ and the Rostrato × Dentato Group see , from abAlready in 1954, the cultivation range of ‘Rostrato’ had become substantially contracted and fragmented. And, although it had completely disappeared from the Comun Nuovo territory, it survived in a few isolated localities of the Po and Venetian Plains , and in some Alpine valleys . In these areas, defined by Our field and literature surveys provided the first comprehensive distributional scenario of beaked maize in northern Italy after the 1954 national collecting campaign promoted by the Stazione Sperimentale di Maiscoltura of Bergamo .Currently, 23 different landraces of beaked maize are cultivated across the study area  together with five crosses involving the genepool of these landraces . No formally improved cultivars were identified. Eighteen landraces  are recorded for the first time in this publication as a result of the ethnobotanical investigation carried out by the authors  and 3.http://www.antichimaispiemontesi.it/; http://www.pignolettorosso.it/; our interviews).The complex of landraces and allied crosses is distributed in six regions  and 22 provinces of northern Italy; one (R20) is also cultivated in the United States , Fig. 1.polenta taragna  rostrata Bonaf., the earliest available name under the ICN .Taking into consideration the historical account of beaked maize in Europe given in the previous paragraph, three of these morphological characteristics constantly appear in all the available descriptions published since Bonafous in  and charhttp://www.antichimaispiemontesi.it/) and original measurements of the accessions stored at the University of Pavia Germplasm Bank  more than 40 cm long, highly branched. Pistillate inflorescences (“ears”) usually one (rarely two) per plant, located at about the middle of the culm; prophyll and leaf sheaths (“husks”) deep green, sometimes purplish-brown. Catoclesia (“ears”) 12–25 cm long, 3.5–5.5 cm wide, cylindro-conical to cylindrical, base slightly enlarged or not, apex rounded to acute; rows 12–18, usually regularly arranged and straight, from widely spaced to packed, resulting in a star-shaped to round ear cross-section respectively; rachis (“cob”) with white or pinkish to dark brownish-purple (“red”) glumes. Caryopses (“kernels”) 8–13 mm long, 7–10 mm wide, 2–5 mm thick, broadly elliptical to broadly obovate, apex from roundish to pointed arch-shaped, usually tapering, in correspondence of the style insertion, into a prominent and prickly beak curved distalwards, sometimes reduced only to the enlarged stylar base; crown smooth or with a shallow to deep indentation; pericarp from bright yellow to deep orange or from red to chocolate- or vinous-brown (“black”), concolor or with a paler  spot of variable extension on the crown due to the presence of floury (“soft”) endosperm; endosperm entirely horny (“flint”) or with a small proportion of floury endosperm (“semi-flint”), yellow  introduced before modern dent hybrids , is charIn order to understand the distribution patterns across time of the current landraces and allied crosses of beaked maize, we arranged them into four different categories . These w (1)Native landraces: cultivated in the same area by, at least, two generations of farmers; we also included within this category landraces whose cultivation has recently been expanded outside of their native range. (2)Recovered landraces: re-propagated from kernels stored ex situ, either in crop genebanks or otherwise . (3)Introduced landraces: cultivation derived from germplasm imported from a different area than the one in which they are currently cultivated; contrary to native landraces that have extended their previous range, introduced landraces cannot be found anymore in their native area from where they were imported. (4)Crosses: resulted from a recent deliberate cross between two landraces. Crosses can be further divided into native and introduced crosses. In the first case, the parental landraces are both native to the area where the cross originated; in the second case, at least one of the parental landraces has been introduced from a different area to where the cross originated.As shown in It is interesting to note that all three crosses are the result of informal crossing between a beaked and a non-beaked flint landrace cultivated in contiguity, then deliberately maintained by individual farmers for specific traits of culinary and aesthetic interest. Similarly, as for the landrace R16, the farmer who originally recovered it is selecting a new line characterized by black and beaked kernels. One of the farmers who is cultivating R5 is likewise selecting a new line provided with red kernels . These ovicinismo”, i.e., “vicinity”, as defined by These considerations are supported by the origin of most OPVs and specifically the Rostrata Group itself, which arose from the informal crossing of different maize types that were cultivated for a prolonged period in close proximity . While for 18 landraces active conservation measures are put in place , for two landraces  the interviewed farmers wished to be supervised by an agronomic institution to help reduce introgression events. For only four  of the 18 landraces in which active conservation measures were observed, those measures follow procedural guidelines prescribed by farmers’ associations or De.Co .The main on-farm conservation strategies to prevent introgression issues are:(1) sowing a long distance, of at least 200 m, from other maize cultivations, especially of hybrid dent corn . In some cases , isolated sites, such as clearings within woodlands or poorly accessible mountain fields, are preferred for the cultivation of beaked maize, in spite of the risk of possible damage from wild animals  and thus yield loss;(2) sowing in different periods from hybrid dent maize to avoid simultaneous flowering (R16);(3) selecting, through mass selection, ears and kernels with the characteristic features of the landrace , for 20 landraces farmers are aware of and/or have directly experienced the issue of dent hybrid introgression, with 18 of them carrying out active measures to prevent it or at least minimize it . The in ex situ conservation status of the Rostrata Group genepool appears satisfactory: for 20 out of the 28 landraces seed samples are maintained in long-term storage in one or more seedbanks . Of these, seven were conserved ex situ for the first time under the framework of the current study . Nowadays, Rostrata Group landraces are still grown across most northern Italian regions, yet this extended distributional area is much more fragmented than it was 60 years ago . NeverthUndoubtedly, cultivation in hill and mountain areas provided natural barriers that limited introgression events, first of all the distance from the Po and Venetian Plains, which host the most widespread cultivation of dent hybrid corn. Mountain areas are less suitable to intensive maize cultivation and the replacement of OPVs by hybrid dent cultivars has historically been slower in mountain provinces than in provinces located in the plains . Some laFrom our investigation it emerged that, after decades of decline, a revival process  involving beaked maize landraces has been occurring since the late 1990s and indeed has been gaining momentum since the early 2000s.Of the 28 landraces investigated, the cultivation of four , whose cultivation ceased in the past , has been re-established since the early 2000s, thanks to seed acquired from agronomic genebanks  or from old ears casually discovered in farms . This ishttp://www.pignolettorosso.it/; our interviews). We are therefore witnessing a shift in beaked maize cultivation that until the late 1990s was mostly designated for own-consumption, while currently it is mainly intended for commercialization. These landraces have survived genetic erosion as heirloom varieties and are now offering new economic opportunities to farmers. In this context, it is interesting to note that besides traditional products made using beaked maize flour, such as polenta and biscuits, new food products for some landraces  are now being experimented with, such as beer, crackers and even pizza or ice cream  and Ark of Taste labels, while not one is listed as a Slow Food Presidium. It appears clear that, besides a few widely recognized landraces, there are several others which are undergoing a revival process via non-governmental means, such as associations of local farmers or millers, constituted around seven landraces  with the aim of promoting products derived from these and to safeguard the true-to-type cultivation  have been registered in the National Register of Conservation Varieties and only three  have been granted a De.Co. (for R21 the De.Co. label is applied not to the landrace itself but to tivation .http://www.antichimaispiemontesi.it/). The Rostrata Group represents one of the most ancient and neglected genepools among this new crop generation, its origin chronologically preceding the improved cultivars of the 1920s and 1930s. The process of revival is contributing to its preservation and, to some extent, is providing an additional income to farmers.Taking into consideration maize cultivation history in Italy from the 19th century up to the present day, marked by three generations of cultivars and landraces , we can In this context, the activities of local farmers, in the role of “custodians” of plant genetic resources need to be encouraged and supported, especially by government  and research institutions. In relation to OPVs, custodian farmers appear in fact to be key figures in the accomplishment of on-farm conservation, whose role is eminent in promoting a dynamic adaptation of landraces to environmental and agricultural changes that, for instance, are being experienced in recent years by maize cultivation across Europe .The first record in this paper of 18 beaked maize landraces previously unknown to the scientific community, also highlights the potential of ethnobotanical surveys in discovering neglected genetic resources (see, e.g., 10.7717/peerj.5123/supp-1Data S1Ethnobotanical interview form used in surveys.Click here for additional data file.10.7717/peerj.5123/supp-2Table S1Click here for additional data file.