This is also a simple scheme to measure the apex angle of an axicon with ease. Using such vortices we have studied non-collinear interaction of photons having orbital angular momentum (OAM) in spontaneous parametric down-conversion (SPDC) process and observed that the angular spectrum of the SPDC photons are independent of OAM of the pump photons rather depends on spatial profile of the pump beam. In the presence of spatial walk-off effect in nonlinear crystals, the SPDC photons have asymmetric angular spectrum with reducing asymmetry at increasing vortex radius.The “perfect” vortex is a new class of optical vortex beam having ring radius independent of its topological charge (order). One of the simplest techniques to generate such beams is the Fourier transformation of the Bessel-Gauss beams. The variation in ring radius of such vortices require Fourier lenses of different focal lengths and or complicated imaging setup. Here we report a novel experimental scheme to generate perfect vortex of any ring radius using a convex lens and an axicon. As a proof of principle, using a lens of focal length  Spontaneous parametric down-conversion (SPDC)1ilθ), where θ is the azimuthal angle. The integer l is called the topological charge or the order of the vortex. It has been observedOptical vortices having phase singularities (phase dislocations) in the wavefront, carries vanishing intensity at the singular point. Due to the screw-like  phase structure around the point of singularity, such beams carry OAM. The characteristic phase distribution of optical vortices is represented as exp is the annular width of the perfect vortex of ring radius governed by the relationwhere, n and α are the refractive index and base angle of the axicon respectively. As evident from Eqn. (3), for given axicon parameters, the radius of the perfect vortex is constant for a lens and linearly varying with the focal length of the Fourier transforming lens.where, l = 6 with annular ring radius continuously varying from 0.3–1.18 mm. This novel experimental scheme can potentially be used as a quick and simple technique to measure the apex angle of an axicon. Pumping a nonlinear crystal using such vortices of different ring radius we have studied the angular spectrum of the down converted photons and experimentally observed that the angular spectrum of the down converted photons is dictated by the spatial profile of the pump but not it’s OAM. However, the asymmetry in the angular spectrum which is detrimental to the entanglement quality of the SPDC sourceHowever, for all practical purposes1217D from the focal plane. The basic principle of the technique is pictorially represented in f–D) behind the lens of focal length, f, is Fourier transformed into perfect vortex at the back focal plane for input vortex beams. The amplitude distribution of the perfect vortex at the back focal plane is given byAccording to the Fourier transformation theorywD = 1.65 × 2woIl can be approximated to13In the current system configuration, the width of the perfect vortex is 2Therefore, Eqn. (4) can be reduced toThe Eqn. (6) has similar functional form as Eqn. (1) with additional quadratic phase factor and a scale factor. As we are dealing with the intensity of the perfect vortex beam at focal plane, the quadratic phase does not make any difference in our current study. The perfect vortex ring is formed at, D → 0, the Fourier transform relation breaks down. Therefore, the value of D can be varied practically within the range of 0 < D < f.As evident from Eqn. (7), the radius of the perfect vortex can be varied simply by moving the axicon away from the back focal plane of the lens. For ring radius l = 1 and l = 2, respectively, at conversion efficiency >95%. Due to limited availability of SPPs producing vortices of order l > 2, using a vortex-doubler setupl = 6. The axicon with apex angle 178° converts the vortex beam of order l into BG beam of the same order. The Fourier transforming lens (f = 200 mm) placed before the axicon with a separation of f-D (D is the distance of the axicon from Fourier plane) produces the perfect vortices at its back focal plane. The 5 mm long β-BaB2O4 (BBO) nonlinear crystal converts the pump photons at 405 nm into degenerate down converted photons at 810 nm in non-collinear phase-matching at 3° with respect to the pump beam direction. Due to circular symmetry, the photons are generated in a cone of apex angle 6° and the photons of each pair are situated in diametrically opposite points. A second lens, f = 50 mm Fourier transforms the generated SPDC ring which is recorded using EMCCD after filtering the pump photon using an interference filter of 10 nm bandwidth centred at 810 nm.The schematic of the experimental setup is shown in f = 200 mm) using a CCD camera with the results shown in l = 1 and l = 5 shown in ρr = 1.18 mm confirming the generation of vortices having annular ring radius independent of topological charge, perfect vortex. To confirm the vorticity and order of the perfect vortex, the vortex beam is interfered with a Gaussian beam at 405 nm with interference pattern shown in second column of l = 1 and l = 5 respectively. Unlike the spiral fringe pattern as observed in the interference of normal vortex beam with Gaussian beam, the spiral fringes in To verify the generation of perfect vortex, we have recorded the intensity profile of the beam at the back focal plane of the Fourier transforming lens  we could not record experimentally the perfect vortex of ring radius, ρr < 0.3 mm by placing the axicon with separation D < 40mm. To avoid such mechanical constrain in recording the vortex ring radius for D < 40 mm, which is beyond the scope of present study, one can easily image the Fourier transforming plane to other measurement planes. On the other hand, further increase in vortex ring radius requires Fourier transforming lenses of longer focal lengths. Using Eq. l = 3 as shown in second row (d–f) of l = 0, 2 and 6 (l = 0 is the Gaussian beam) with the results shown in α = 1° and refractive index, n = 1.5302 at 405 nm) we found a clear mismatch between theoretical (solid line) and experimental results. The theoretical and experimental variation of ring radius with axicon distance have slope of 9.23 × 10−3 and 7.33 × 10−3 respectively. From the experimentally measured slope (7.33 × 10−3) we found the apex angle of the axicon to be 178.40 slightly higher than the value 178° presented by the manufacturer. To verify the manufacturing inaccuracy in the apex angle of the axicon, we have repeated the same experiment for three different laser wavelengths . As expected, the annular ring radius increases with axicon position (D) away from the Fourier plane for all three wavelength at a slope of ~6.83 × 10−3, 7.05 × 10−3 and 7.05 × 10−3 for 532 nm, 632 nm and 1064 nm respectively. Using the refractive indices of the BK-7 glass we found the axicon to have apex angle of 178.4° ± 0.03° similar to the value measured previously. Such study also proves that the present experimental scheme ]r, where, ωdc is the frequency of the down converted photons, c is the velocity of light in free space and f is the focal length of the Fourier transforming lens. In the current study we have used two topological charges, l = 0 (Gaussian beam) and l = 3 and varied their ring radius ρr for different axicon positions  and recorded the angular spectrum of the down converted photons with the results shown in ρr = 0.3, 0.75 and 1.18 mm for l = 0 and l = 3 respectively. Kx and Ky are the transverse momentum components of the down converted photons. As evident from the ρr of both the topological charges, l = 0 and l = 3, the down converted photons have identical transverse profiles with intense inner and outer rings and intensity gradient in between. Therefore, it can be concluded that the OAM of the input pump beam has no effect in the transverse distribution of the down converted photons. However, it should be noted that the sum of the OAMs of signal and idler photons of each pair will be equal to the OAM of the input pump photonL tanρo in the nonlinear crystal of length, L and birefringence parameter, ρo. For L = 5 mm and ρo = 67.44 mrad of the BBO crystal, the L tanρo value is calculated to be 0.34 mm. As a result, we can expect asymmetric transverse distribution in down converted photons for pump beam radius, ρr = 0.3 mm.To study the contribution of OAM in the angular spectrum of the down converted photons, we pumped the nonlinear crystal (BBO) placed at the Fourier plane after the axicon using perfect vortices of different orders and ring radii. The angular spectrum or transverse momentum distribution of the down converted photons, obtained from the Fourier transformation of the generated photons using a convex lens of focal length, ξ is defined as ξ = 1 − a/b, where a and b representing the separation between the inner and out radii on left and right sides of the angular spectrum of the down converted photons respectively as shown in inset of the ξ, for different size of the perfect vortex of order l = 3. As evident from the ρr > L tanρo (>0.34 mm), we still observe a certain degree of asymmetry in angular spectrum at higher values of ρr. However, for ρr = 1.18 mm (~3 × L tanρo) we have observed symmetric (ξ < 10%) angular spectrum of the down converted photons. Such study ascertain the need of proper beam diameter of the input structured beam  depending upon the birefringence and length of the nonlinear crystal for entangled photon sources.However, the asymmetry in the transverse momentum distribution of the down converted photons is detrimental for entangled photon sourcesl = 1 and l = 2, respectively, at conversion efficiency >95%. Due to limited availability of SPPs producing vortices of order l > 2, we have used a vortex-doubler setupl = +1 (say). The λ/4 plate having its axes at 45° to its polarization axis converts the polarization of the beam into left circular polarization. The mirror, M, reverses both the polarization handedness (left circular to right circular) and sign of the vorticity (l = +1 to −1) of the reflected beam. The right circularly polarized beam on return pass through the λ∕4 plate gets converted into vertical polarization. To the return beam (l = −1), the direction of phase variation of the SPP1 is opposite to that of the forward pass. Therefore, the return beam acquires additional spiral phase resulting total vorticity, l = −2, twice the phase winding of the SPP placed inside. Since the return beam have vertical polarization, it gets reflected by the PBS2. Using different combinations of SPP1 and SPP2, placed inside and outside of the vortex-doubler we have generated optical vortices of orders  up to l = 6. An antireflection coated 1” diameter axicon made of BK-7 glass having apex angle 178° is used to convert the vortex beam of order l into BG beam of the same order. As shown in f = 200 mm) placed before the axicon with a separation of f-D (D is the distance of the axicon from Fourier plane) produces the perfect vortices (2O4 (BBO) is used as the nonlinear crystal for down conversion of the pump beam (e → o + o) non-collinear phase-matching to produce degenerate signal and idler photons at 810 nm at an angle 3° with respect the pump beam. Due to the circular symmetry, the photons are generated in a cone of apex angle 6° and the photons of each pair are situated in diametrically opposite points. A second lens, f = 50 mm Fourier transforms the generated SPDC ring .


Engaging adolescents in decisions about their health may enhance their compliance with treatment and result in better health outcomes. Treatment outcomes in attention-deficit/hyperactivity disorder (ADHD) are rarely evaluated from the adolescents’ point of view. There is also concern that adolescents with ADHD may not have insight about the impacts of their disease. This article describes research conducted to understand the experiences of adolescents with ADHD and how the research was used to develop an adolescent self-report instrument.This research involved an iterative process to ensure content validity and was conducted in the following stages: concept identification from literature reviews and interviews with teachers and clinicians; concept elicitation interviews with adolescents with ADHD and their caregivers, review of existing instruments; development of a new instrument and cognitive interviews. Experts in instrument development and translation and clinical practitioners in ADHD also participated.A conceptual framework to measure the impact of ADHD on adolescent functioning identified from concept identification research informed concept elicitation interviews with 60 adolescents with ADHD and their primary caregivers. In the interviews, adolescents discussed difficulties with performing activities in various contexts: school, home, leisure activities and social interactions. Caregivers provided additional insights. The instrument review revealed that none of the existing instruments were suitable to collect data on the elicited concepts; therefore, a new instrument was developed. Revisions were made to the format and content of the instrument (a daily diary) based on feedback received from cognitive testing with 15 adolescents.Our research helped to obtain a comprehensive understanding of the impacts of ADHD on adolescent functioning, to inform the development of a new instrument for measuring outcomes. Adolescents were able to discuss the impact of ADHD on their lives in concept elicitation interviews and report the impacts of ADHD on a self-report instrument. The new instrument developed to reflect the perspective of adolescents with ADHD can be used to supplement outcome assessments in clinic and research settings. Scientific advocacy for the use of such measures can be valuable to measure outcomes meaningful to adolescents with ADHD and the clinical community. Treatments for attention-deficit/hyperactivity disorder (ADHD) aim to address symptomatic, syndromatic and functional outcomes of the disease , 2. MediIn addition to their changing environments, as children grow older they are given more responsibilities by their caregivers, and often make decisions about medication use. Expectations about outcomes of treatment may be different for adolescents with ADHD compared with those of younger children or adults with the condition. Adolescents’ beliefs about ADHD and attitudes to medication have also been shown to drive their adherence to treatment , 9, 10, However, the evaluation of treatments for ADHD in clinical trials have mainly used clinician or caregiver-reported assessments about the symptoms of ADHD, such as the ADHD-Rating Scale , and ConThe objective of this study was to identify impacts of ADHD that are most relevant to adolescents to help develop a strategy for evaluating treatment outcomes in this patient group. The study also aimed to explore the feasibility and options available for collecting adolescent self-reports that capture these impacts to monitor and evaluate outcomes of treatment.concept identification from literature reviews and interviews with teachers and clinicians, concept elicitation interviews with adolescents with ADHD and their caregivers, development of conceptual frameworks, review of existing instruments, development of a new instrument, and cognitive interviews with adolescents to test and refine the instrument. The methods and results from each of these stages of research are presented in chronological order. Authors were additionally mindful of the criteria for reporting qualitative studies checklist suggested by Tong et al. , again, will get very upset with these neighbor kids because something-something he has perceived that they’ve done, um, and that is better though now than it used to be. A few years ago he would-he might beat them up, um, but now he just might, I don’t know, walk away or say something rude to them or something, it’s much less, um, physical than it used to be.” Another caregiver reported: “I think, um…I think [<Son>] has social challenges. I don’t think he thinks he does, um, I think they are definitely related to his A-ADHD, um, and that’s because he gets in your face when he’s not on medication and he’s jumping around and moving around and it’s just-it’s irritating. And I could see where his peers would get tired of that fast, where he can’t just have a conversation.” Further examples are provided in Table Parents typically provided additional insights into the specific difficulties that their adolescents faced as a result of other symptoms of ADHD (impulsivity and hyperactivity). For example, a caregiver of a 15-year-old boy with ADHD reported on the difficulty their child had because of being impulsive, but was also able to report on change to this difficulty over time: “Most adolescents described feelings of stress related to their performance of tasks or social interactions because of their ADHD, using terms such as guilt, worry, anxiety, stress/stressed out and irritable to describe their emotions. In the school setting, adolescents provided examples of stress with completing classroom work properly and on time, remembering things, following instructions, behaving well during class, interacting with teachers and peers. Adolescents reported feeling stressed in school owing to not understanding the work, not keeping up with the rest of their class during lessons, and getting behind in school work largely owing to their difficulty with keeping focused on lessons. Adolescents provided examples of stress, such as getting ready for the day on time in the mornings, completing homework or chores in the evenings, and interacting with family members. Parents used the term anxiety to describe the adolescents’ experiences and reported on difficulties that adolescents had with the control of their emotions, mostly anger, in terms of temper outbursts. A few caregivers also mentioned excessive sadness in the adolescent.ADHD significantly impacts aspects of adolescent functioning. Adolescents and caregivers provided different perspectives of the adolescents’ experiences of ADHD. For example, in an interview in Cohort 1 where the adolescent and his caregiver were interviewed separately, the caregiver reported that her son with ADHD was in a tagging crew , and on occasion she has had to phone the police regarding her son to help discipline her child’s illegal activities. In the individual interview with the son, despite being probed about getting into trouble, he did not mention this.While caregivers were more open about reporting on incidents where adolescents had experienced difficulties, with prompts adolescents did not refute these incidents. This is illustrated in the quote below, during a discussion about the impact of ADHD on leisure activities from a Cohort 2 interview, where the caregiver and adolescent were interviewed at the same time.So just because he’s doing it and liking it doesn’t mean he’s happy about it in the end.” Interviewer: “Why would you say that is then?” Adolescent: “Um, well, like sometimes when I’m playing FIFA I will keep-it will start to get boring after I play a couple of games. So then I’ll go outside and ride my bike. And so I can’t just stay on one thing for like the whole day.”Parent: “….The concept tracking grid to evaluate saturation of concepts showed that across interviews, adolescents reported similar difficulties in the context of home, school and leisure, supporting saturation.The concepts identified through concept elicitation interviews were used to revise the preliminary conceptual framework developed previously based on the concept identification work. The revised framework was shared with clinicians and was modified further based on their feedback, to ensure clinical relevance and to highlight concepts that were more useful to capture the outcomes of pharmacological interventions for ADHD (the context of use for the new instrument). This resulted in a few revisions to the conceptual framework for measuring the concept of interest. For example, clinicians suggested that some of the concepts reported by adolescents and their caregiver as an impact of ADHD, such as emotional lability, were likely to be part of the psychopathology of the disease rather than an impact of the core symptoms of ADHD. Clinicians also helped to focus the concepts in the framework on the impact of the symptoms of ADHD on function, rather than the functional impairments noticed by most caregivers of adolescents without ADHD. The results also showed that social functioning in adolescents was closely linked to the social settings to which they are exposed, rather than just being an individual with ADHD. Clinician interviews had highlighted previously that social functioning may not respond to pharmacological treatments alone. Therefore, the concept to evaluate adolescents’ experiences with ADHD was focused on difficulty with social interactions, rather than more distal concepts about their social functioning , as these would be influenced by environmental and social factors other than ADHD. Based on the results above, the following concepts were considered as core concepts to collect data from adolescents to understand the impact of ADHD on adolescent functioning, and relevant to evaluate outcomes of pharmacological treatment. The final conceptual framework for evaluating the impact of ADHD on everyday activities and social interactions in adolescents with ADHD is illustrated in Fig. Adolescents reported that the level of difficulty varied at different times of the day. They also reported that they would find it hard to recall their difficulties more than a few days in the past.To determine whether published tools that measure functional outcomes in ADHD covered the concepts that are meaningful and important to adolescents with ADHD, a review was conducted to identify tools used in clinical trials in adolescent ADHD. PRO instruments were identified based on a review of select conference abstracts, clinical trials.gov, the Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID), and the Patient Reported Outcomes Measurement Information System (PROMIS) database. The contents of the tools were reviewed to identify a) the best coverage of concepts emerging from the concept elicitation work and b) methods used to generate the items and assess if they meet criteria for content validity required for PRO tools used to support label claims , 17. ThiThirty-four tools were identified from the review; 11 had adolescent-specific versions. An item ‘pool’ was developed, which included the items selected from instruments that cover the concepts from the conceptual framework. Adolescent-specific versions largely included concepts similar to the child versions, with some adjustments to match developmental stage, and were more likely to be self-reported.In reviewing the content of the tools, the Weiss Functional Impairment Rating Scale-Self (WFIRS-S), a self-reported scale to evaluate symptoms and functioning in adults with ADHD, covers seven conceptual domains , and had the best coverage of concepts. However, the tool has some shortcomings in terms of suitability of use for evaluating outcomes of pharmacological interventions from the adolescent’s perspective. Firstly, item generation for the tool was not supported by concept elicitation work with an adolescent population. Additionally, the recall period of the tool is the ‘past month’, which may not capture the variability of the impact of symptoms on functioning as experienced by varying demands of the days for adolescents and would be challenging for adolescents to complete as they mentioned difficulty recalling impacts over longer periods of time. Finally, the WFIRS-S collects information about the frequency of impacts rather than the level of difficulty of functioning experienced and reported by the adolescent with ADHD. Based on the review, development of a new instrument was deemed the most appropriate strategy.The findings from concept elicitation interviews and results of instrument review suggested the need for an instrument: a) with a shorter recall period; b) that collected information about the level of difficulty and effort required by the adolescents; and c) that evaluates the impact of ADHD on functioning in different contexts  from the adolescent’s perspective. The tool review found no such instrument to fill this need.Best practice guidelines were used to guide the process of generating items . This inlevel of difficulty or effort required to do their school work, leisure activities and tasks at home. Response options for the instrument were thus selected to enable adolescents to specify how hard it was to do/how much effort was required, to function. Two types of scales for obtaining response options – a numeric rating scale (NRS) and a visual analogue scale (VAS) – were developed for testing in cognitive interviews.Concept elicitation research suggested that the impact of ADHD on functioning was reported by adolescents in terms of the To capture the variability of the adolescent experience over the course of a day, and to ensure shorter recall periods to address recall bias, the instrument was designed to be administered twice daily (at the end of the school day and in the evening before bed). An electronic platform was selected to facilitate the ease of completion, enhance compliance , include examples of terms on the screen, and also ‘pop-up’ definitions if the participant requires additional information. At the end of the school day, adolescents were asked to indicate the magnitude of difficulty or effort required to do the following – ‘how hard was it to’: get ready for the day in the morning, do school work, behave well in the classroom, interact with family members in the morning and/or interact with friends and teachers at school. Another item asked how stressed they felt about school work that day (seven items). At the end of the day, adolescents were asked to indicate the magnitude of difficulty or effort required to do the following – ‘how hard was it to’: do homework, chores, sports or hobbies and interact with friends and family. Another item asked how stressed they felt about doing their homework that evening (six items).The instrument also includes items that ask the adolescent to indicate their overall level of stress at three time points in the day – morning, school day and evening, and some optional items that can help to characterize the adolescents’ experience such as: “Did you leave home on time this morning?” and “Did you have all the materials that you needed to complete your homework or other work for school?”. Figure A translatability assessment and a lexibility (reading level) evaluation were conducted on the draft instrument prior to testing the instrument to ensure that the items were translatable and that the reading level was appropriate for adolescents aged 13–17 years. The instrument was finalized for cognitive testing. The translatability assessment helped to identify words or phrases that were structurally or culturally problematic when translated into different languages for potential use in multicountry clinical trials. This included revisions to the diary such as spelling out times of the day as an alternative to a 24-hour clock, as well as rephrasing statements and replacing words for clarity such as ‘to reach transportation for school’ instead of ‘to get transportation to school’.Cognitive interviews were conducted to gain insight into subjects’ interpretations of the items, match the intent of the items and assess whether any critical content (concepts or items) had been omitted from the instrument. All interviews also explored the suitability and appropriateness of response options and recall periods, and also preferences for an NRS or a VAS to select responses to items . The patFeedback received from adolescents with ADHD during the cognitive interviews was used to improve the questionnaire. The analyses of data from these interviews included examining: 1) the clarity of the items within the scale; 2) participants’ interpretation of the items; 3) ease of questionnaire completion; 4) comprehensiveness and relevance of the measure; and 5) appropriateness of the format, response scales and recall period. The analysis also focused on the instructions and content coverage of the questionnaires to ensure items fully captured the impact of ADHD on functioning. After the completion of Round 1 (n = 8 interviews), an interim analysis was conducted using the criteria listed, and modifications were made accordingly and retested during Round 2 interviews (n = 17 interviews) before finalizing the instrument.Twenty-five adolescents were interviewed across the two rounds of interviews. Similar to the sample for concept elicitation interviews, all of the adolescents included in the cognitive interview study were currently taking medication 100 %) and most described their ADHD as mild (64 %). A smaller percentage of adolescents in the cognitive interview study (28 %) reported having specialized assistance at school compared with those included in the concept elicitation study (40 %)  suggested changing the name from diary. Most children with ADHD continue to suffer impacts associated with the disease into adolescence, despite receiving treatment. This has been attributed to the increasing demands placed on adolescents at school and at home , 6. WhilConcepts related to the impacts of ADHD and methodological considerations identified from concept identification phase were used to design the study and informed the data collection approach. As low concordance between reports by parents and adolescents was reported in the literature , the quaThe qualitative study provided evidence supporting adolescents’ ability to self-report on the impact of ADHD. Concept elicitation interviews identified functional concepts of impairment including: difficulty performing tasks; difficulty related to interactions; and feelings of stress about difficulty with school work and performing tasks. The findings are similar to Goodman et al. , with reReview of the instruments developed previously demonstrated incomplete coverage of the important concepts for assessing the impact of ADHD on functioning identified during the concept identification and concept elicitation studies. Therefore, a novel instrument was developed for adolescent self-report, focusing on outcomes that are likely to respond to successful medical intervention in the context of a clinical trial. Inclusion of clinicians’ perspective helped to ensure the clinical relevance of the tool. For example, collecting data on areas where adolescents may be able to perceive improvement , rather than areas where improvements are the consequence of external factors . The development of this new tool followed the processes as outlined by a USA regulatory agency , as wellThe generation of new items for the PRO instrument captures adolescents’ experiences during different times of the day. The daily variability in adolescents’ schedule, coupled with the variation of experiences and difficulties owing to ADHD, as well as the adolescents’ inherent difficulty with remembering past experiences, suggests that data regarding these concepts may need to be captured more frequently to support the need for adolescents to respond to questions based on a shorter timeframe. None of the existing PRO tools include a short recall period . A short recall period was used to prevent reporter bias based on clinician report and research suggesting that ADHD impairs working memory .For adolescents with ADHD the magnitude of difficulty with performing the task and the effort to perform the task appeared to be more relevant than the actual occurrence or absence of the functional impairment. Understanding the benefit of treatment in terms of whether or not it reduces the level of effort to perform tasks may resonate better with adolescents, when evaluating outcomes of treatment in clinical trials or monitoring outcomes in clinical practice. The response options that reflect changes in the level of difficulty or effort required by the adolescents if their ADHD symptoms were controlled assess two key measurement aspects of ADHD functioning. This includes the focus on the performance of daily activities rather than the perception of their performance, removing any bias in adolescents’ ability to complete a task per FDA guidance. Secondly, the focus on capturing the level of difficulty required to complete a task, rather than frequency of impairment, has the potential to provide more meaningful measurement of behaviour and functioning.The content validity of the instrument was established through cognitive interviews where adolescents completed the instrument, providing insights on the selection and meaning of their responses. Results from these interviews suggest that adolescents had valuable insights into the impact of ADHD, and could report on these impacts, contradicting previous opinion that PIB may inhibit ADHD adolescents’ ability to self report . The resThe new instrument can be used to capture the adolescent perspective of the impact of ADHD on functioning. It can also supplement traditional clinical assessments used to monitor adolescents’ experiences in clinical setting, as well as in clinical studies, hence allowing evaluation of outcomes that are meaningful to adolescents. However, there are a few limitations to the research that should be considered when evaluating the application of the instrument. To start, the sample of adolescents interviewed was relatively homogenous, with white males making up a large majority of those adolescents interviewed in the study. Most of the participants were recruited from only two states  within the USA, which may not reflect the general population of ADHD participants. Additional research on the concept elicitation approach to compare concept elicitation with and without caregivers, and in different countries, ethnicities and cultures is warranted. The diagnosis and sub-types of ADHD Table  were basThis study provides a comprehensive understanding of the impacts of ADHD on adolescent functioning, which has been used to inform the development of a new instrument for measuring outcomes. Adolescents were able to discuss the impact of ADHD on their lives in concept elicitation interviews and report the impacts of ADHD on a self-report instrument. A new instrument, that was developed based on these findings, can be used to supplement assessments in clinic settings and research, and to evaluate outcomes that are meaningful to adolescents. Scientific advocacy for the use of such instruments can be valuable to measure outcomes that are meaningful to the ADHD adolescents and the clinical community. To continue to build on this research foundation, additional quantitative work should be done to validate the concepts and instrument to facilitate improved measurement of treatment effects among adolescents.


Attention deficit hyperactivity disorder (ADHD) is a common heritable psychiatric disorder with a worldwide prevalence of 5%. The etiology of ADHD is still incompletely understood, but several studies, consistently indicate the strong role of genetic factors on this disorder. The aim of this study was to determine the effect of three SNPs rs11122319, rs11122330 and rs6675281 in the etiology of ADHD in an Iranian childrenDISC1 gene with ADHD in Iranian population. Two hundred fourthy subjects composed of 120 patients and 120 healthy controls were included and tetra-primer ARMS PCR technique was used for genotyping all selected SNPs.In this research work, for the first time, we investigated the association of three SNPs  in the P value = 0.008, OR= 1.5837, 95% CI= 1.1012 to 2.2776).We found differences in genotype and allele distributions of rs 6675281 polymorphism between our patients and controls. The A, T and A alleles were the more frequent alleles in rs11122319, rs6675281 and rs11122330 polymorphisms in both case and control groups respectively. The TT genotype was more frequent in control group compared to patients. (DISC1 gene as a susceptibility locus for ADHD and indicate that rs6675281 polymorphism is a susceptibility factor for ADHD for the first time in children reported in an Iranian population in this part of the world.Our findings strengthens the role of  Attention deficit hyperactivity disorder (ADHD) is a disorder affecting neurodevelopment, characterized by hyperactivity, inattention and impulsivity behavior. ADHD is a relatively common disorder with a prevalence rate of about 3-5% among prepubescent elementary school children.4The high prevalence of Attention deficit hyperactivity disorder necessitates the understanding of the etiology, as well as the development of approaches for diagnosis and treatment of this disorder.5DAT-1, DRD4, DRD5, 5HTT, HTR1B and SNAP-25 genes and the ADHD.7However the etiology of ADHD is not clearly understood, it’s a highly heritable disorder of childhoodDISC1) is a candidate gene causing susceptibility in a spectrum of psychiatric disorders.DISC1 has the highest expression of brain tissue in the hippocampus and the cerebral cortexDISC1 is located on chromosome 1q42, and originally identified in a Scottish pedigree by observing a breakpoint causing a chromosomal translocation. Spanning over 410 kb it includes 13 exons and encodes a cytosolic scaffold protein which acts in collaboration with several proteins with different functions.DISC1 have been shown to be associated with some mental disorders such as depression, bipolar disorder, schizophrenia, and schizoaffective disorder in several independent populations and according to its function, DISC1 may contribute to susceptibility to psychiatric disorders.DISC1 gene. In one study performed in 2013 it was shown that disc1 variants have associations with ADHD in Norwegian and Spanish patients.11Disrupted-in-schizophrenia1  with 50 µl of reaction volume and final primer concentration of 0.2 mM using the Ampliqon® master mix (1.5 mM MgCl2) and the primers shown in p value less than 0.05 was considered as statistically significant for the tests. We used Statistical Software Package for the Social Science  to perform statistical analysis.Fisher exact test was used to compare genotype and allele frequencies between ADHD cases and controls. Odds ratio (OR) together with 95% confidence interval (CI) was estimated; and a Three single nucleotide polymorphisms, rs11122319, rs11122330 and rs6675281 were examined in this study for genotype and allele frequencies in patient and control groups. The polymorphisms were investigated in 120 ADHD patients and 120 healthy controls with mean age of 9.5 ± 2.5 and 9 ± 2.9 respectively. There was no significant differences in age and gender distributions between two groups and the genotype distributions of all three polymorphisms did not deviate from Hardy-Weinberg equilibrium expectation.P value = 0.008, OR= 1.5837, 95% CI= 1.1012 to 2.2776). For other two polymorphisms, no significant differences in genotypic and allelic distributions were shown. There was no linkage disequilibrium between three SNPs. p value cut-off to consider each as significant is 0.016 (Bonferroni correction). Hence rs6675281 with p values 0.008 and 0.005 remained to be significant  gene, located in a 415 kb region on chromosome 1qOne hundred twenty children with ADHD and 120 healthy controls were selected for each of three polymorphisms and result revealed that the rs6675281 polymorphism had marginal association with ADHD in our sample population of children. The TT genotype of the mentioned SNP showed differences in distribution in patient and control groups and were more frequent in healthy controls. Hence, it have negative association with ADHD. In the analysis of allelic frequencies, the results showed allelic association for this polymorphism as well. Therefore, there was no other significant differences in genotypic and allelic frequencies for other polymorphisms between two groups.DISC1 variants on ADHD, Jacobsen and colleagues reported the association of rs6675281 and rs11122330 polymorphisms with ADHD in 694 ADHD cases and 735 normal controls in Norwegian population.13In the first and only existing study regarding the effect of DISC1 polymorphisms, the rs11122319 polymorphism was showed to be associated with mean temporal cortical thickness in patients with history of psychosis by.DISC1 variants, it was implicated that the rs6675281 polymorphism’s alleles affect the expression level of DISC1, so that the T allele carriers had significantly higher levels of DISC1 expression in comparison with C allele carriers.23In other previous studies performed on DISC1, more frequency of T allele in our normal samples seems to be logical. Our results replicated the involvement of DISC1 and its variants in the etiology of ADHD. According to limited number of our ADHD samples due to limited accessibility to valid cases. to our knowledge, our study is the first research investigation of DISC1 in ADHD and it adds ADHD to the traits possibly associated with DISC1 variation in children in Iran and Middle East. Although DISC1 for a long time was considered a susceptibility gene for psychotic disorders, more recent findings have shown that it is involved in general neurodevelopment and signaling, and it is possible that unknown functional variants may predispose an individual for a range of different mental illnesses. More functional genomics studies could be cited and discussed with review article entitle DISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders.25According to the overall reports, our results of rs6675281 single nucleotide polymorphism was in consistence with several other studies, and given the association of T allele of this SNP with higher expression of This research work needs much more data in different populations and ethnic groups to further support of the role of DISC1 in development of ADHD and draw firm conclusion.


Legislative changes that came into effect in the UK in April 2012 gave nurse independent prescribers (NIPs) the power to prescribe schedule 2–5 controlled drugs. Therefore, suitably qualified UK nurses can now independently prescribe any drug for any medical condition within their clinical competence. The potential benefits of independent nurse prescribing include improved access to medications and more efficient use of skills within the National Health Service workforce. This review explores the published literature (to July 2013) to investigate whether the predicted benefits of NIPs in mental health settings can be supported by empirical evidence, with a specific focus on nurse-led management of patients with attention-deficit/hyperactivity disorder (ADHD). The most common pharmacological treatments for ADHD are controlled drugs. Therefore, the 2012 legislative changes allow nurse-led ADHD services to offer holistic packages of care for patients. Evidence suggests that independent prescribing by UK nurses is safe, clinically appropriate and associated with high levels of patient satisfaction. The quality of the nurse–patient relationship and nurses’ ability to provide flexible follow-up services suggests that nurse-led ADHD services are well positioned to enhance the outcomes for patients and their parents/carers. However, the empirical evidence available to support the value of NIPs in mental health settings is limited. There is a need for additional high-quality data to verify scientifically the value of nurse-delivered ADHD care. This evidence will be invaluable in supporting the growth of nurse-led ADHD services and for those who support greater remuneration for the expanded role of NIPs. In April 2012, UK legislative changes gave nurse independent prescribers (NIPs) the power, for the first time, to prescribe schedule 2–5 controlled drugs Table . Many beIn this review, we explore the impact of the extended prescribing rights of UK NIPs on nurse-led services for patients with attention-deficit/hyperactivity disorder (ADHD) and examine the potential benefits of expanding the delivery of nurse-led ADHD services in the UK. In 2005, a Cochrane review evaluated the impact of substituting nurses for doctors in primary care, concluding that appropriately trained nurses can provide care of equally high quality to that provided by primary care doctors and can achieve equally good health outcomes for patients  or the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (hyperkinetic disorder), be associated with at least moderate psychological, social and/or educational or occupational impairment and occur in two or more important settings including social, familial, educational and/or occupational settings , but it is noteworthy that DSM-5 differs from its predecessor in requiring several inattentive or hyperactive symptoms to be present before 12 years of age, compared with the presence of symptoms that cause impairment prior to the age of 7 years in DSM-IV . Diagnosis can also be complicated by the fact that patients with ADHD often have co-existing psychiatric disorders. However, high levels of diagnostic certainty can be achieved through use of diagnostic rating scales in combination with a developmental history, observation, and the assessment of family and other risk factors , working across a range of therapy areas, reported that they made the diagnosis on most occasions in their prescribing practice  and pharmacist independent prescribers  using the Medication Appropriateness Index  and PIPs (n = 48) were making clinically appropriate prescribing decisions  is safe and clinically appropriate Black . Latter n = 566)  Black . However6) Black . As withStudies indicate that NIPs have high levels of confidence in their prescribing abilities  believed that they worked within their competency, and most agreed that they had adequate knowledge of side effects, dosage, drug interactions, withdrawal effects and physical health monitoring  of UK-based patients with ADHD were found to be at least as satisfied with the care received from ADHD advanced nurse practitioners as with that previously provided by medical staff (Laver-Bradbury and Harris n = 28) were almost entirely positive. Some of the parents completed the General Health Questionnaire  and the Parenting Sense of Competency Questionnaire  before and after attending support groups. Using the GHQ, 12 parents had an initial score greater than 12 , whereas, 4 weeks after starting to attend the support group, only six parents had a score greater than 12 . The legislative changes permitting the prescribing of controlled drugs by NIPs provide the opportunity for nurse-led ADHD services to offer a complete package of care to individuals with ADHD, facilitating enhanced engagement with patients and carers and improved continuity of care, which would be expected to lead to increased levels of client satisfaction.As with other chronic health conditions, improving adherence to treatment is key to maintaining effective control of symptoms and problem behaviours associated with ADHD. Adherence to ADHD medications is consistently higher among patients involved in clinical trials than among those receiving treatment in the community , Europe (n = 3), Asia (n = 1) and Africa (n = 1), with seven studies focused on patients who were HIV-positive and the remaining three assessing patients with depression, arthritis and hypertension . However, the data available to assess the quality of nurse-delivered management of patients with ADHD are, so far, limited. The quality of nurse-led and doctor-led management was compared in patients with ADHD who had been previously diagnosed and titrated to a stable medication dose by a doctor (Foreman and Morton n = 13) before and after attending nurse-led support groups  found that only half of respondents felt supported in their role  working in UK mental health settings, which found that 60 % agreed that there were shortfalls in training and supervision  demonstrated that a 10-day psychopharmacology course, costing £300 per participant, led to statistically and clinically significant gains in knowledge (Jones et al. As a possible solution to the potential training shortfall, one study of UK mental health NIPs (Many NIPs believe that the additional levels of expertise and responsibilities associated with their prescribing role should be recognised in their job description and financially rewarded (Earle et al. Despite these identified barriers and reservations, there is evidence to indicate that NIPs who are actively prescribing have higher levels of job satisfaction than those who are not (Cousins and Donnell The symptoms and functional impairments associated with ADHD can negatively impact many aspects of patients’ lives and also present challenges for their parents, carers, teachers and employers. ADHD can be effectively managed, but this requires a multimodal treatment approach which can be time-consuming and labour intensive for healthcare providers. Legislative changes that came into effect in April 2012 permit UK nurses to prescribe schedule 2–5 controlled drugs, including stimulant medications for the treatment of ADHD, independently. This means that nurse-led services in the UK can now provide a full package of care for patients with ADHD.We believe that UK ADHD nurses possess the required specialist skills and experience to deliver high-quality, holistic care for patients with ADHD. We also believe that nurse-led services have the potential to enhance the experience of patients with ADHD and their carers, and to deliver improved patient outcomes compared with standard care models. While multiple small-scale studies support the potential benefits of nurse independent prescribing, there are few large-scale studies and even fewer studies that directly compare nurse-delivered care with that of medical colleagues. Importantly for this review, none of the identified large-scale studies have specifically assessed nurse-delivered care for patients with ADHD, with evidence limited to a few small-scale studies. Latter et al.  indicate


Attention-deficit/hyperactivity disorder (ADHD) is a common behavioral and neurocognitive disorder in school-age children. Methylphenidate (MPH) is the most frequently prescribed CNS stimulant for ADHD. The aim of this study is to evaluate the changes in intelligence quotient and domains of neurocognitive function after long-term MPH treatment of Taiwanese children with ADHD.The Wechsler Intelligence Scale (WISC-III) was administrated twice at an interval of at least one year for all 171 subjects (6–12 years) and 47 age- and gender-matched children without ADHD. The ADHD-Rating scale and Clinical Global Impression-Severity (CGI-S) were also used at the time of enrolment, and at 6 months and one year later.Taiwanese children with ADHD had lower Verbal IQ (VIQ) and Full IQ (FIQ) and performed poorly on several subtests of the WISC-III, including Similarities, Vocabulary, and Coding, compared to healthy children without ADHD. After one year of MPH treatment, significant decrements in all scores of the ADHD-Rating scale and CGI-S and increments in several domains of the WISC-III, including FIQ, VIQ, PIQ, Perceptual Organization Index (POI), Picture Completion, Picture Arrangement, Object Assembly, and Digit Span were observed. When the ADHD children under MPH treatment were subdivided into two age groups (6–8 years and 9–12 years), significantly better performance in some subtests and subscales of the WISC-III  was found in the 6–8 years age group.Long-term MPH treatment may improve the neurocognitive profiles of the ADHD children, as seen in their performance in several subtests and in the IQ scores on the WISC-III. And this improvement had no correlation with the decrement of ADHD symptoms. Starting stimulant treatment at as young an age as possible is advised due to the greater benefits in the 6–8 years age group, as seen in this study. More research in this area is also needed to confirm these results. Attention deficit hyperactivity (ADHD), one of the most common behavioral and neurocognitive disorders , is charMethylphenidate (MPH), a kind of central nervous system (CNS) stimulant, is the most frequently prescribed medication for ADHD, and its clinical efficacy is well established . The effIn Taiwan, a high prevalence rate of ADHD was noticed about ten years ago , but theWe collected ADHD children from the outpatient clinics of a medical center in northern Taiwan from December 2005 to 2006. Inclusion criteria were: age 6–12 years; and a clinical diagnosis of ADHD based on the relevant DSM-IV diagnostic criteria and standardized clinical assessments, as determined by experienced board-certificated child psychiatrists. Study approval was obtained from the Institutional Review Board of Chang Gung Memorial Hospital. Written informed consent was obtained from the parents of each child and children following an explanation of the study.The diagnostic assessment of ADHD were performed by two senior child psychiatrists, who administered structured interviews using the Chinese-language version of the Schedule for Affective Disorder and Schizophrenia for School-Age Children , epidemiSince executive function could be screened by the WISC , we chosThe WISC-III is a standardized intelligence test suitable for children and adolescents aged 6–16 years. It contains 13 subtests, namely Information, Similarities, Arithmetic, Vocabulary, Comprehension, Digit Span, Picture Completion, Coding, Picture Arrangement, Block Design, Object Assembly, Symbol Search and Maze. VIQ, PIQ and full IQ (FIQ), and their scores can be calculated based on these subtests. The verbal comprehension index (VCI), perceptual organization index (POI), freedom from distractibility index (FDI), and processing speed index (PSI) were also calculated from these subtests. The WISC-III was used when the participants first enrolled in the study. Repeated WISC-III tests were administered for those who stayed in the study and received CNS stimulant treatment for one year. The second WISC-III test was administered at least one year from the first test. All participants were free from medication for at least one week prior to the first and the second administration of the WISC-III.The ADHD-Rating scale is a structured interview completed by the investigator based on information from the parents and child. Each of the items has a 4-point response scale, and each item explores one of the 18 criteria outlined in the DSM-IV to diagnose ADHD. Higher scores indicate greater severity of ADHD. Initial evaluation was scored when the ADHD children were enrolled, and again at 6 months and one year into treatment.The CGI-S uses a 7-point scale with responses ranging from 1  to 7 (the most severely ill patients). The scale was filled out at initial intake, and at 6 months and one year into the study, coinciding with the administration of the ADHD-Rating scale.To compare the differences between healthy children without ADHD and children with ADHD in their performance on the intelligence test, we recruited 47 age-matched children (6–12 years) from surrounding schools in the community by contacting the teachers. Inclusion criteria included healthy children, as reported by the parents, and the absence of ADHD symptoms. All children in the control group were evaluated at the “child developmental evaluation center” of the hospital, where physical, neurological and mental evaluations were performed by the same specialists that saw the suspected ADHD children. The exclusion criteria for the control group were the same as those for the ADHD group.The variables of sample characteristics, scores on the ADHD-Rating scale and CGI-S, and profiles of neurocognitve performance evaluated via the WISC-III between the healthy normal controls and the ADHD children were compared using two sample t-tests and the chi-square test. The changes in the ADHD-rating scale and CGI-S and in performances on the WISC-III before and after MPH treatment in the ADHD group were compared using the paired t-test. The correlation between the changes in the severity of ADHD symptoms and performance on the WISC-III was analyzed via Pearson's correlation coefficient. All tests were performed using SPSS 15.0, with a 2-tailed significance level of 0.05.A total of 171 children with ADHD were included in our study.Compared to the healthy children, the ADHD children had significant differences in their scores on the ADHD-Rating scale Table , includiOf the 171 ADHD children, 130 received MPH treatment. The 41 ADHD children without MPH treatment were younger (p < 0.01) and had less severity on the ADHD-Rating scale, including hyperactivity (p < 0.01) and total (p < 0.05) scores and on the CGI-S (p < 0.01), than those under MPH treatment. However, there was no significant difference in performance on the WISC-III between these two groups.In the MPH treatment group, 103 participants (79%) continued in the study beyond one year. Children who were lost to follow-up during the period of MPH treatment had the same severity of ADHD symptoms, but had better performance in FIQ (p < 0.05), VIQ (p < 0.05), PIQ (p < 0.05), Arithmetic (p < 0.01), and Vocabulary (p < 0.001).The 103 participants who stayed in the study beyond one year were administered the ADHD-Rating scale and the CGI-S at 6 months and one year. Psychometric measures using the WISC-III were also completed for the 103 participants again at the end of one year. All subscores on the ADHD-Rating scale, including inattention (p < 0.001), hyperactivity (p < 0.001) and total (p < 0.001), and the CGI-S (p < 0.001) decreased significantly for ADHD children after drug therapy. Significant increments in the FIQ (p < 0.001), VIQ (p < 0.05) and PIQ (p < 0.001) scores were also found in the MPH treatment group. Among the subtests of the WISC-III, significant improvements in performance were found in Picture Completion (p < 0.01), Picture Arrangement (p < 0.01), Object Assembly (p < 0.05), and Digit Span (p < 0.05). The POI (p < 0.001) score also improved significantly after drug therapy Table .ADHD is often comorbid with learning disorders (LD), which would influence performance on the WISC-III. We subdivided the ADHD children with MPH treatment into two groups. One group included 19 ADHD children comorbid with LD and the other, ADHD children without LD. However, we did not find a significant difference between the two groups in the changes in ADHD symptoms and in the WISC-III after MPH treatment.We compared the differences between ADHD children with/without MPH treatment for one year. The results showed that there was a significant increase in FIQ (p < 0.001), VIQ (p < 0.05), PIQ (p < 0.001), Picture completion (p < 0.001), Picture arrangement (p < 0.01), Object assembly (p < 0.05), Digit span (p < 0.05) and POI (p < 0.001) among the ADHD children who received MPH treatment. However, there were no significant changes in performance on the WISC-III among the ADHD children not receiving MPH treatment. The sample size of the ADHD children who received and did not receive MPH treatment was 103 and 17, respectively.The ADHD children under MPH treatment were subdivided into two age groups (6–8 years and 9–12 years). The pre-treatment data of the 6–8 years age group were found to be significantly higher in inattention (p < 0.01), hyperactivity (p < 0.05), and total scores (p < 0.01) on the ADHD-rating scale and CGI-S (p < 0.01), and significantly lower on the Similarities subtest of the WISC-III (p < 0.01) Table . After oWhen further subdividing the group of ADHD children under MPH treatment comorbid with or without LD into two age groups (6–8 years and 9–12 years), similar results could be noted. More improvement with statistical significance in the performances of Similarities (p < 0.01), Comprehension (p < 0.05) and Object Assembly (p < 0.05) was found in 6–8 years age group.No significant correlation was found between the changes in performance on the WISC-III  and the severity of ADHD symptoms as measured by the ADHD-Rating scale and CGI-S Table .Similarly, there were no significant associations between the changes of WISC-III and the baseline ADHD severity and CGI scores in the MPH treatment group Table .In this study, children with ADHD had lower VIQ and FIQ than healthy children without ADHD. The findings in this study showed that FIQ was approximately 9 points lower in children with ADHD than in healthy children. This is compatible with the results of a previous meta-analytic review, which reported that ADHD groups performed at an average of 9.15 FIQ points lower than the control group . We alsoThe benefits to cognitive function after MPH treatment were noted in many studies -34, but There are no recommendations regarding the optimal period for ADHD drug treatment. According to the results of this study, the degree of improvement in ADHD symptom severity was not significantly different relative to the patient's age on receiving MPH treatment. On the other hand, significantly better performance in some subtests and subscales of the WISC-III  was noted in the 6–8 years age group. This suggests that it would be best to start MPH treatment for ADHD at a younger age. However, previous studies have not found that younger age groups obtained more benefits in various aspects than older age groups as a result of MPH treatment. Thus, more research is needed to corroborate this finding and to reach a conclusion.It has been hypothesized that attention deficit in ADHD children would substantially influence IQ , so imprst and 2nd administration of the WISC-III was not long enough to ignore the practical effect without controversy. Sixth, other treatments  associated with MPH treatment were often performed in clinical practice, but the interactions and their possible effect on the WISC-III was not followed up in this study.There are several limitations in this study. First, the sample enrolled in the study did not include all patients with ADHD, so the findings might not be applicable to the entire population of ADHD patients. Second, the sample size in the study was relatively small, particularly for the control group, and some WISC-III subtests  were not administered to the control group. Therefore, the statistical power in this study was limited in its ability to detect the changes from pre- to post-treatment and the differences between ADHD and healthy children. Large-scale studies using integrated psychometric measurements are needed. Third, the majority of children with ADHD were male, so the influence of sex could not be ruled out. Fourth, this was not a randomized controlled trial and whether to start MPH treatment or not was based on clinical evaluation and most importantly the opinions of the parents of the ADHD children. Fifth, the interval between the 1st and 2nd administration of the WISC-III was given at least one year apart, thus reducing the possible practical effect to a limited degree [Although many limitations have been noted, a number of strengths can also be found in this study. First, real-world children with ADHD were sampled and given an appropriate dose of MPH in line with clinical guidelines. Second, the 1d degree ,40. AlthAccording to the findings in this study, we suggest that long-term MPH treatment may improve neurocognitive profiles, which were shown in the performance of the ADHD children on several subtests and in IQ scores of the WISC-III. And the improvement had no correlation with the decrement of ADHD symptoms and baseline ADHD severity. Starting stimulant treatment at as young an age as possible is advised due to the greater benefits seen in the 6–8 years age group. But more research using a controlled sample to replicate the findings is needed.The authors declared that they had no competing interests and received no financial support for this study.CST, YSH, KBY, MHT and SMC conceived, designed and participated in the study. CLW and FMH analyzed the data and assisted in result interpretation. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/330/prepub


We performed this study to longitudinally compare rates of stunting, wasting and underweight among low birthweight (LBW), non-LBW, and/or small-for-gestational age (SGA) and non-SGA infants in Leyte, The Philippines and factors that predicted catch up. Birthweights of 357 infants born in Leyte, The Philippines were obtained within 48 hours of delivery and infants were evaluated at one, six and 12 months. Newborns were classified as LBW, SGA, or both. We derived length-for-age, weight-for-length and weight-for-age Z-scores using WHOAnthro. Generalized estimating equations models were used to compare the differences in prevalence and mean Z-scores for these growth and nutritional outcomes, with separate models made with LBW and SGA as distinct primary predictors. We compared the longitudinal risk of stunting, wasting and underweight during infancy among LBW versus non-LBW and SGA versus non-SGA infants, while also evaluating key potential confounding, explanatory and modifying covariates. Overall, 9.0% of infants were born prematurely, 14.0% of infants were LBW and 22.9% were SGA. LBW infants had significantly increased odds of stunting, wasting and underweight persisting to 12 months of age, and SGA infants had significantly increased odds of stunting and underweight. LBW and SGA infants had higher rates of weight-for-length gain in the first month of life. Maternal educational attainment and exclusive breastfeeding decreased the risk of stunting and undernutrition. In this setting, LBW and SGA infants have higher rates of growth stunting and undernutrition during the first year of life and do not exhibit catch-up growth by 12 months of age.NCT00486863 In low resource settings, undernutrition during infancy is thought to greatly increase the risk of infant and early childhood mortality . Poor grStudies have demonstrated that low birthweight (LBW) and small-for-gestational age (SGA) are risk factors for both linear growth stunting and undernutrition among young children . Specifiin utero, often culminating in an SGA newborn [The prevalence of LBW deliveries ranges from 12–25% in low-income nations compared to 7% in higher-income nations. In affluent populations, most LBW infants are born premature, while in low-income countries the majority are full-term infants who have experienced growth restriction  newborn , 9, 10. th percentile of a healthy reference curve for the newborn’s sex and gestational age (GA). SGA may occur, however, due to the pathologic process of intrauterine growth restriction (IUGR), whereby a fetus does not reach its in utero growth potential, or as a result of normal variability whereby a fetus achieves its in utero growth potential, which is constitutionally small. The availability of the International Fetal and Newborn Growth Consortium for the 21st Century standard (INTERGROWTH-21th) to determine SGA, rather than reliance on United States derived reference curves, has been demonstrated to decrease the percentage of newborns categorized as SGA [A significant challenge to our understanding of the influence of SGA on post-natal morbidity and growth trajectories is that these newborns represent a heterogeneous group. Specifically, most studies define SGA as a birthweight that is less than the 10d as SGA , 12. ThiThe primary objectives of this study were to compare rates of stunting, wasting and underweight at one, six and 12-months-old among LBW, non-LBW, SGA and non-SGA infants born in Leyte, The Philippines. Additional objectives included i) assessment of differences in growth velocity across birthweight status groups during specific age “windows,” ii) determining the timing of growth and nutritional catch-up where this occurred, and iii) elucidating other risk factors  for growth faltering and undernutrition during infancy. Quantification of these relationships may further emphasize the need for prenatal interventions to reduce the risk of LBW and SGA births, as well as post-natal interventions to optimize catch-up growth and nutrition in resource poor settings.Schistosomiasis japonicum as described [This study utilizes data collected as part of an NIH-funded double blind randomized controlled trial (RCT) of Praziquantel given at 12–16 weeks gestation  and a Thrasher Fund supported study of the infants born to these women. The RCT enrolled 370 otherwise healthy pregnant women from rice farming villages in northeastern Leyte, The Philippines with singleton pregnancies who were infected with escribed . As partescribed . Of noteth percentile for GA using the INTERGROWTH-21th [As part of the study protocol, all mothers gave birth at a municipal health center or were referred to Remedios Trinidad Romualdez Hospital if indicated. Newborns were weighed within 48 hours of delivery on a Tanita model BD-585 portable scale  accurate to 10g, and all birthweights with the exception of one were obtained within 24 hours. LBW was defined as weight <2.5 kg and prematurity as birth <37 weeks gestation. SGA was defined as birthweight <10WTH-21th . UltrasoInfants were assessed at RTR hospital at one, six and 12-months-old. They were seen by the study pediatrician who conducted a history, physical examination and assessed length, weight and head circumference. Recumbent length was measured using a pediatric stadiometer  as per Gibson . WHOAnthMaternal educational status was defined as having attained a high school degree or greater level of education versus less than high school completion. At the one, six and 12-month follow-up visits, mothers were asked about infant feeding practices, which were categorized as exclusive breastfeeding, bottle feeding or mixed.t test or Wilcoxon rank-sum test for continuous variables and Fisher’s exact or Chi-square test for categorical variables. To assess the effects of LBW and SGA on LAZ, WLZ, and WAZ and length, weight-for-length, and weight gains, as well as the probability of stunting, wasting and underweight, we implemented generalized estimating equations (GEE) models with an exchangeable correlation structure and robust standard error estimation. This approach was used to compare differences in growth and nutritional parameters longitudinally during infancy, comparing infants born in distinct birthweight categories while adjusting for within-subject correlation. These models capture distinct outcomes  at three timepoints for each infants and relate each of these outcomes to time varying predictors at the corresponding timepoint, as well as non-time varying covariates such as sex. Finally, we employed GEE models to assess the effects of LBW and SGA on absolute gains in length and weight as well as weight for weight-for-length in the first year of life.Group differences  were determined by using a Student’s P values <0.2 in the univariable models were considered for inclusion in multivariable models. Multivariable models for stunting, wasting and underweight were built by performing a backward elimination process until only significant variables remained.GEE models were also used to identify other risk factors for adverse growth and nutritional outcomes as well as effect modifiers of the relationship between birthweight category and risk of stunting, wasting and underweight throughout infancy. Distinct models with LBW or SGA as the primary predictor were evaluated for each of the nutritional outcome measures, as we could not include the non-independent variables of SGA/LBW in the same models. LBW and SGA status (in distinct models) and potential confounders with P values <0.05 were considered to be significant, except in univariable analyses.All statistical analyses were performed using SAS 9.4 . Infants with an acute or chronic medical condition or malnutrition diagnosed during the newborn period or during the infant follow-up study were referred for care. The pregnancy trial and the infant follow-up studies were separately approved by both the Rhode Island Hospital Institutional Review Board in Providence, RI and the Ethics Review Board of the Research Institute of Tropical Medicine in Manila, The Philippines. All maternal participants of the study provided written informed consent approved by both review boards.in utero. Birthweight was ascertained for 361 of 365 live births and 357 infants enrolled in the infant follow up study. Of these, 14.0% were LBW and 22.9% were SGA (Of 370 pregnant women enrolled, there were five fetal deaths were SGA . ApproxiAt each age, significantly more LBW infants remained stunted and underweight compared to non-LBW infants and the same patterns were observed among SGA and non-SGA infants . SignifiThe significantly higher weight-for-length gains of LBW and SGA infants between birth and one month of life  diminishIn the univariable GEE models, the odds of stunting throughout infancy were significantly increased when infants were male, LBW, SGA and bottle or mixed fed versus exclusively breastfed . The oddIn the multivariable GEE analyses , the finOur results suggest that LBW and SGA infants in this setting do not catch up to non-LBW and non-SGA infants, even by age 12 months, with respect to most measures of linear growth and nutritional status. A slightly greater weight gain among both LBW and SGA infants was limited to the first month of life, explaining some convergence in WAZ and WLZ by one–month-old, but with little catch up thereafter. The lack of any significant differences in linear growth velocity during any window led to significant difference in risk of stunting and LAZ throughout infancy. This differential growth pattern is likely due to rapid soft tissue gain in the first few months of life, that did not, however, allow catch up growth . These fth percentile had over twice the risk of stunting and 1.45 times the risk of wasting compared to the other newborns throughout the first 18 months of life [The persistently increased odds of growth stunting and undernutrition in LBW and SGA infants that we observed are consistent with studies conducted in other resource-constrained settings in Africa and Asia , 23–26.  of life .in utero [Importantly, studies in the United States have shown that IUGR and SGA infants have lower nutritional Z-scores during infancy and early childhood than infants with the same birthweight who were born prematurely , 27–30. in utero , 31. GivIn addition to LBW and SGA, our study identified other risk factors for stunting, wasting and underweight. Breastfeeding was shown to be a protective factor for decreasing odds of stunting among all infants regardless of birthweight status. This is consistent with the well-described benefits of exclusive breastfeeding in Filipino infants and other infants in LMIC settings , 32–35. in utero [Male sex was also a significant risk factor for stunting in LBW infants and for underweight in LBW and SGA infants. In previous studies in Filipino infants, males were more likely to become stunted in the first year of life, and females in the second year of life . Males min utero , 38, 39.in utero –43. Matein utero . ImportaImportantly, other studies of LBW infants in the Philippines have reported that postnatal growth patterns are significantly related to social economic status . Our resth rather than Western-based reference curve for SGA also makes it more likely that these SGA infants experienced IUGR. In addition, the longitudinal design allowed for better assessment of causality in determining risk factors for undernutrition and growth faltering during infancy.Though previous studies have examined growth and nutritional outcomes in the LMIC setting, this study adds a determination of SGA that is more likely to be accurate based on the use of 12–16 week ultrasound for GA determination. The use of the INTERGROWTH-21in utero growth potential and did not experience IUGR. As above, use of a healthy reference curve comprised of newborns from multiple different nations, including LMICs, mitigates this concern somewhat. With respect to etiology of SGA, limitations with respect to our ability to diagnose infections, particularly viral infections that might impact growth in utero, preclude identifying these common etiologies. In addition, the definition of pre-eclampsia employed at the time of study inception required two elevated blood pressures separated by four hours and most refused to wait. Though many women were diagnosed at delivery with pre-eclampsia based on elevated blood pressure, lack of application of standard definition did not allow us to determine the percent of newborns who were SGA due to this very common etiology. Finally, these infants were only followed until 12-months-old, however, additional studies of these children at five years of age will further elucidate long-term growth and nutritional catch up.Limitations of this study include the fact that mothers and infants were from a rural region of The Philippines, which may limit generalizability. In addition, though we considered SGA births as newborns who likely experienced IUGR during pregnancy, it is possible that some of these newborns, in fact, reached their Though LBW and SGA infants in this setting exhibit increased weight and weight-for-length velocity in the first month of life, they remain at significantly higher risk of undernutrition and do not catch up to non-LBW and non-SGA infants by 12-months-old. Importantly, infants who were LBW were actually less likely to be exclusively breastfed at six-months-old. Lower maternal educational attainment continues to influence the risk of undernutrition in this setting among all infants, emphasizing the need for education regarding exclusive breastfeeding and health literacy in order to the decrease the risk of stunting and undernutrition in these high risk groups.


DRD4 and SLC6A3 were identified in all sibling-pairs following standard protocols. Groups were compared adjusting independent general linear models for the exponential and normal components from the ex-Gaussian analysis. Identified trends were confirmed by the non-parametric Jonckheere–Terpstra test. Stair-like distributions were observed for μ (p = 0.036) and σ (p = 0.009). An additional “DRD4-genotype” × “clinical status” interaction was present for τ (p = 0.014) reflecting a possible severity factor. Thus, normal and exponential RTisv components are suitable as ADHD endophenotypes.Intra-individual variability of response times (RTisv) is considered as potential endophenotype for attentional deficit/hyperactivity disorder (ADHD). Traditional methods for estimating RTisv lose information regarding response times (RTs) distribution along the task, with eventual effects on statistical power. Ex-Gaussian analysis captures the dynamic nature of RTisv, estimating normal and exponential components for RT distribution, with specific phenomenological correlates. Here, we applied ex-Gaussian analysis to explore whether intra-individual variability of RTs agrees with criteria proposed by Gottesman and Gould for endophenotypes. Specifically, we evaluated if normal and/or exponential components of RTs may (a) present the stair-like distribution expected for endophenotypes  without familiar history of ADHD) and (b) represent a phenotypic correlate for previously described genetic risk variants. This is a pilot study including 55 subjects (20 ADHD-discordant sibling-pairs and 15 TD children), all aged between 8 and 13 years. Participants resolved a visual Go/Nogo with 10% Nogo probability. Ex-Gaussian distributions were fitted to individual RT data and compared among the three samples. In order to test whether intra-individual variability may represent a correlate for previously described genetic risk variants, VNTRs at  Symptom-based diagnostic systems such as the current versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM)  and the Taking this into account, it has been proposed to replace symptom-based phenotypes by quantifiable markers of liability or “risk” for a specific disorder . These mIn the last few years, researchers have started to explore the potential of some neuro-cognitive and electrophysiological/radiological markers as endophenotypes for attentional deficit/hyperactivity disorder (ADHD). Among them, intra-individual variability  seeTraditionally, intra-individual variability has been estimated by collapsing responses across the entire time interval of the task, resulting in a single point parameter such as the standard deviation of the response time (RTSD) or the coefficient of variation of the response time (RTCV), which should capture and represent how data spread around the mean value. This method implies to lose a significant amount of specific information regarding the distribution of response times (RTs) along the task, with eventual effects on statistical power when comparing RTisv among clinical groups. Particularly, this method does not recognize the asymmetrical positive skew that occasional lapses in attention are expected to produce in the RTs distributions .During the last decade, the field has moved toward new statistical approaches aiming to obtain more complete and specific characterizations of the RTisv. Among these approaches, the ex-Gaussian analysis on the RTs has provided enlightening results regarding the dynamic nature of intra-individual variability in ADHD. Basically, the ex-Gaussian analysis is based on the convolution of an exponential and a Gaussian function, obtaining three parameters: μ (mu), corresponding to the mean of the normal component, σ (sigma), corresponding to the SD of the normal component, and τ (tau), which describes the mean of the exponential component. When fitting ex-Gaussian distributions to RT data, greater values for τ indicate a higher frequency of excessively long RTs . In geneDRD4) and for the dopaminergic transporter 1 (SLC6A3/DAT1). We choose the aforementioned genetic risk variants based on previous evidence suggesting that RTisv may be associated to dopamine dysfunction  when compared to ADHD patients and typically developing children (TD) without family history of ADHD, and so that, whether intra-individual variability may follow the hypothetical distribution postulated for endophenotypes. As a second step, we explored whether RTisv may represent a phenotypic correlate for previously described genetic risk variants for ADHD in the genes encoding for the dopaminergic receptor D4  and gender distribution .In order to evaluate eventual differences in regards to the RT distribution observed among ADHD patients, their non-affected siblings, and TD without family history of ADHD, we evaluated a total of 55 subjects, corresponding to 20 discordant sibling-pairs and 15 unaffected children from the general population. Sibling-pairs were originally recruited as part of a parallel genetic association study started in 2003 . This std-amphetamine or methylphenidate, both in doses ranging 10–30 mg/day. A wash-out period of 24 h free of medication was required before the neuropsychological assessment.Inclusion criteria for ADHD children were as follows: ADHD combined subtype according to DSM , age betIn the case of the groups composed by non-affected siblings and TD from the general population, inclusion criteria were age between 8 and 13 years old and absence of ADHD or any other psychiatric morbidity according to DSM-IV criteria. Additionally, a negative familiar history of ADHD was required in the TD group. Familiar history of ADHD was explored in first degree relatives (siblings and parents) of TD participants by means of a semi-structured interview assessing presence/absence of DSM-IV criteria during childhood. Children with neurological deficit at physical examination and/or abnormal baseline electroencephalography (EEG) were excluded from the study. All aforementioned inclusion/exclusion criteria were assessed according to current ADHD diagnosis guidelines by a competent specialist (child psychologist or child neurologist).We only included ADHD patients and their unaffected siblings for genotyping analysis. This design was chosen in order to control for an eventual population stratification effect. As additional advantage, discordant sibling-pairs share most of the psychosocial and familial factors that might interact with a potential genetic predisposition. Thus, for the genetic part of the study, 40 participants (corresponding to 20 siblings-pairs) were assigned to “Risk” or “Non-Risk” genotype groups accordingly with the criteria described in Section “DRD4 and SLC6A3 loci according to the protocols described by Lichter et al.  to identify the VNTR of the r et al.  and by Cr et al. , respectr et al. .Details on the Go–NoGo task performed in this study have been previously reported by our group . BrieflyR statistical package (Data corresponding to the response time (RT) in front of all Go stimuli were obtained from each subject. Only correct responses were computed in order to determine the parameters of the ex-Gaussian distribution of RT, according to the data-analysis protocol originally described by Leth-Stevenson et al. . Additio package , and μ, p-values after post hoc analysis are reported.In order to compare the characteristics of ex-Gaussian distributions among ADHD children, their non-affected sibs, and TD from the general population (TD), we adjusted independent general linear models for μ, σ, and τ, using age and sex as co-variates and “clinical group”  as an ordinal variable, with ADHD as the highest ordinal value and TD as the lowest. Additionally, we confirmed the statistical significance of the detected trends by means of the non-parametric Jonckheere–Terpstra test to evaluate trend in the data . Significance was defined as alpha = 0.05. For multiple comparisons, DRD4 and SCL6A3 genes, on the other hand, we applied three consecutive approaches. First, eventual differences in μ, σ, and τ between the genetic risk and non-risk groups were preliminary explored by means of non-parametrical methods (Wilcoxon Rank Test). In a second step, significance levels were adjusted by age, sex, and clinical status by means of general linear models. Finally, the effect of an interaction between the “clinical status (presence/absence of ADHD) and genotype group (risk/control) was explored by general linear models for μ, σ, and τ, with the independent variables “genetic risk group” (risk versus control group), age, sex, clinical status, and “genetic risk group × clinical status” interaction. As mentioned above, in order to control for population stratification, only sib-pairs were included for genetic analysis.When comparing the characteristics of the ex-Gaussian distributions regarding to the presence/absence of genetic risk variants previously linked to ADHD in the n = 11; 3 of them in homozygous state) or 2R . This group included 18 subjects and 11 subjects presented ADHD among them. There was no association between allele possession for Exon 3 VNTR of DRD4 and clinical status . We chose to include carriers of the 7R and 2R alleles in the “risk group” based on previous reports of association between ADHD and these variants in different populations  and the “control” or “non-risk” was constituted by subjects with any other genotype . The latter group comprised 14 participants with 9R/10R genotype and 1 homozygous for the 9R allele. There was no association between allele possession for 3′ UTR VNTR of SLC6A3 and clinical diagnosis of ADHD, χ2(1) = 0.28, p = 0.59.“Genetic risk groups” were defined as follows: (a) For DRD4; the “control” or “non-risk” group was comprised by homozygous for the DRD4 4-repeat allele. A total of 22 subjects were assigned to this group and 9 of them were ADHD patients. The “risk” group, on the other hand, was constituted by carriers of at least one copy of alleles 7R  ForAll procedures performed as part of this study were approved by the Ethics Committee of the Pontificia Universidad Catolica de Chile. The study was fully explained to children and their parents, and they both agreed to participate by signing written consent forms.p-value = 0.015). Since models were adjusted with ADHD as the highest ordinal value and TD as the lowest, we can assume that μ presented with the stair-like distribution typically expected for endophenotypes. A similar interesting trend was observed for σ , although it did not reach statistical significance after controlling for age and sex . We did not find a statistically significant effect for “clinical group in the models adjusted for τ. Similar results were obtained using Jonckheere–Terpstra test to evaluate the trend ADHD > non-affected sibs > TD .Figure DRD4 (2A) and SCL6A3 (2B). In the case of DRD4, subjects were classified depending on the presence/absence of VNTR variants previously linked to ADHD in the exon III of DRD4, with carriers of at least one copy of the 7R or 2R allele considered as the risk group and homozygous for 4R as the controls/non-risk group. The ex-Gaussian distribution adjusted among subjects from the genetic risk group is more skewed than the ex-Gaussian distribution for DRD4-4R homozygous, which is expressed as a bigger value for τ . Interestingly, linear models demonstrated a statistically significant effect of the “genotype group” × “clinical status” interaction exclusively on τ  a generalized slowing down of the responses times (reflected at the μ component), (b) an increased variability throughout the complete distribution (reflected at the σ component), or (c) an increased number of abnormally slow responses (reflected at the τ component). The aforementioned distinction could be mechanistically relevant, since it has been suggested that larger τ values may reflect inconsistent effort and fluctuations in attention , while larger σ components may reflect deficits in motor timing and/or impaired response preparation , 25. Notp-value = 0.014). This result suggests that – in the context of a relatively long and high demanding inhibition task – attentional lapses may be predominately expressed on those ADHD patients carrying at least one copy of the 7R or 2R VNTR variants of DRD4. This finding is in accordance with other works, which associate DRD4 with severity of ADHD symptoms of impulsivity , low probability for the NoGo stimuli (10%), and shot inter-stimuli interval (1000 ms). In these conditions, the μ and σ components obtained after fitting ex-Gaussian curves on the RT data from ADHD patients, healthy siblings, and TD children without family history of ADHD, showed the stair-like distribution expected for endophenotypes. This finding suggests that not only ADHD children but also ADHD healthy relatives (or at least a subpopulation of them) may present alterations in response preparation and motor timing. By contrast, our experimental conditions are not particularly conducive to the appearance of attentional lapses. Hence, it was expected that we failed to find the aforementioned distribution in the case of τ component, due to our short inter-trial periods. Nonetheless, the second part of our analysis showed a statistically significant effect of the “genotype” × “clinical status” interaction for DRD4 on τ  seemed to be affected by the DRD4-genotype. Overall, our results emphasize the advantages of introducing new statistical methods oriented to reach a dynamic and fine-grain characterization of performance measures obtained from well-validated tasks in the analysis of new candidate-endophenotypes in psychiatric disorders. New studies are needed in order to confirm our results under different attention and inhibitory loads.Study/experiments design: Marcela Patricia Henríquez-Henríquez, Francisco Aboitiz, and Francisco Rothhammer. Experiment execution: Marcela Patricia Henríquez-Henríquez, and Francisco Javier Zamorano. Genotyping: Hugo Henríquez and Francisco Rothhammer. Data analysis/statistical analysis: Marcela Patricia Henríquez-Henríquez and Pablo Billeke. Interpretation of results and discussion: Marcela Patricia Henríquez-Henríquez, Pablo Billeke, Francisco Aboitiz, and Francisco Rothhammer. Contributed reagents/materials/analysis tools: Marcela Patricia Henríquez-Henríquez, Pablo Billeke, Hugo Henríquez, and Francisco Rothhammer. Elaboration of the manuscript: Marcela Patricia Henríquez-Henríquez, Pablo Billeke, and Francisco Aboitiz. Critic lecture of the manuscript: Marcela Patricia Henríquez-Henríquez, Pablo Billeke, Francisco Javier Zamorano, Francisco Rothhammer, and Francisco Aboitiz.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.