Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with substance use disorders (SUD). The combination of ADHD and SUD is associated with a negative prognosis of both SUD and ADHD. Pharmacological treatments of comorbid ADHD in adult patients with SUD have not been very successful. Recent studies show positive effects of cognitive behavioral therapy (CBT) in ADHD patients without SUD, but CBT has not been studied in ADHD patients with comorbid SUD.This paper presents the protocol of a randomized controlled trial to test the efficacy of an integrated CBT protocol aimed at reducing SUD as well as ADHD symptoms in SUD patients with a comorbid diagnosis of ADHD. The experimental group receives 15 CBT sessions directed at symptom reduction of SUD as well as ADHD. The control group receives treatment as usual, i.e. 10 CBT sessions directed at symptom reduction of SUD only. The primary outcome is the level of self-reported ADHD symptoms. Secondary outcomes include measures of substance use, depression and anxiety, quality of life, health care consumption and neuropsychological functions.This is the first randomized controlled trial to test the efficacy of an integrated CBT protocol for adult SUD patients with a comorbid diagnosis of ADHD. The rationale for the trial, the design, and the strengths and limitations of the study are discussed.http://www.clinicaltrials.gov as NCT01431235.This trial is registered in  Adult Attention Deficit Hyperactivity Disorder (ADHD) is highly frequent in Substance Use Disorder (SUD) patients ,2. SUD pOther treatment options for ADHD such as cognitive behavioral therapy (CBT) or EEG neurofeedback have not been investigated yet in ADHD patients with a comorbid SUD. However, three recent randomized controlled trials reported a positive effect of CBT in adult ADHD patients without substance abuse -17. In tThe current study is designed to test the efficacy of an integrated CBT protocol combining a standardized motivational interviewing and coping skills training program for SUD with a CBT program for ADHD. The CBT program for SUD is based on evidence-based CBT protocols addressing substance abuse ,19 adaptApart from ADHD outcomes, we are also interested in the potential effects of this integrated treatment on substance use. According to the self-medication hypothesis , substanThe aims of this trial are to test the acceptance, feasibility, efficacy and cost-effectiveness of an individual integrated CBT protocol for SUD patients with a comorbid diagnosis of adult ADHD. The integrated CBT protocol aims to address both SUD and ADHD.The primary research question is:1. Does adding a CBT program aimed at reducing ADHD symptoms to a cognitive behavioral treatment as usual for SUD (TAU), result in a decrease of self-reported ADHD symptoms in adults with SUD and comorbid adult ADHD compared to TAU only at the end of treatment and at two months follow-up?Secondary research questions are:1. Does adding a CBT program aimed at reducing ADHD symptoms to TAU result in a greater reduction of self-reported substance use in adults with SUD and comorbid adult ADHD than TAU only?2. Does adding a CBT program aimed at reducing ADHD symptoms to TAU result in a greater decrease of self-reported depression and anxiety and a greater increase in quality of life than TAU only?3. Does adding a CBT program aimed at reducing ADHD symptoms to TAU result in a greater improvement in neuropsychological functions than TAU only?4. What are the comparative costs per gained quality adjusted life year (QALY) for the integrated CBT protocol and TAU only?5. Are baseline characteristics  predictive of treatment response to either TAU or integrated CBT (patient-treatment matching)?We hypothesize that patients in the integrated treatment condition will achieve stronger reductions in ADHD symptoms than patients in the TAU only condition at the end of treatment and at 2 months follow-up. Moreover, we expect participants in the integrated treatment condition to have lower scores on self-reported substance use, depression and anxiety and higher scores on quality of life than participants in the TAU only condition at the same time points. We also expect the integrated CBT protocol to result in greater improvements in performance on neuropsychological tasks, and we expect the integrated CBT protocol to have a higher cost-utility than TAU only. At this moment, we have no explicit hypothesis about the baseline characteristics that might be predictive of treatment response in terms of a decrease of ADHD symptoms in the integrated treatment condition or the TAU condition (patient-treatment matching).Participants are (self)referrals seeking treatment for their substance use problems at the Jellinek, a large addiction treatment center in Amsterdam, the Netherlands. To be eligible for the study, patients have to meet the following inclusion criteria: after intake allocated to outpatient treatment unit, aged 18–65 years, full command over the Dutch language, current DSM-IV diagnosis of any substance use disorder other than nicotine dependence only, and a comorbid DSM-IV diagnosis of ADHD with persisting symptoms meeting diagnostic criteria in adulthood. Patients with pathological gambling and other behavioral addictions are not included.Patients with severe neurological  or psychiatric disorders  requiring medication, are excluded from the study. Patients with a borderline personality disorder are also excluded and referred to adequate treatment for this condition. Patients currently using ADHD medication (e.g. methylphenidate) are allowed to participate provided that they are on a stable dose and no medication changes are planned for the duration of the trial.During the standardized intake and treatment allocation procedure at the Jellinek, patients are screened for ADHD. Screen positive patients are invited for a semi-structured diagnostic interview with a specially trained psychologist to assess the presence of a DSM-IV diagnosis of adult ADHD. If ADHD, persisting in adulthood, is diagnosed, the patient is informed about the possible treatment options and receives oral and written information on the treatment study. If the patient is interested in participation, he or she is contacted by telephone by one of the investigators for further information. If the patient wants to participate in the study, informed consent is signed during the next visit. In the current study, no  ADHD medication is provided.Patients are randomized to receive either Treatment As Usual directed at the treatment of SUD (TAU only) or TAU plus CBT sessions aimed at reducing ADHD symptoms (integrated treatment condition). Treatment allocation is performed randomly by online application of a biased-coin randomization (minimization). In this way, we aim to ensure that trial arms are balanced with respect to three baseline characteristics: gender, use of ADHD medication (yes/no), and type of SUD diagnosis . Neither patients nor therapists or investigators are blinded for the treatment allocation.Figure Participants in the TAU only condition receive outpatient substance abuse treatment using a treatment program for SUD that is implemented nationally in the Netherlands ,21. The Participants in the experimental treatment condition receive an integrated treatment for SUD and ADHD, combining the main elements of the CBT program for SUD with CBT interventions for ADHD from the ‘Mastering your adult ADHD’ program developed by Safren et al. ,23. The For the integrated treatment condition, the ADHD treatment program and the CBT program for the treatment of substance use disorders were integrated in the following way. We adapted the original ADHD treatment into a more condensed version, in which the core elements of planning and organization skills are presented to the patients in five sessions. In another six sessions from the CBT program directed at the treatment of SUD, 15 minutes are used each session to discuss homework assignments on the ADHD themes and to evaluate the learned skills. Similarly, in the five ADHD sessions, 15 minutes are used to discuss homework assignments on SUD themes. In this way, attention to the training of planning and organizational skills is given in 11 sessions in total. The contrast between the two approaches thus concerns five extra sessions ‘net-time’ on ADHD related issues in the integrated treatment protocol, plus the fact that ADHD symptoms are at least briefly discussed in 11 sessions. Sessions are planned weekly on a fixed time and day as much as possible. The outlines of the control condition (TAU only) and integrated treatment protocol are described in Table Both TAU only and integrated treatment sessions are delivered by therapists who received formal training and supervision in delivering protocolized CBT for SUD and have extensive experience of more than eight years. All therapists received four hours additional training for the CBT interventions targeting ADHD symptoms. Weekly supervision of both integrated treatments and TAU only by an experienced staff member (EV) is provided for the duration of the trial.With the exception of some self-report questionnaires, most assessments are conducted in face-to-face contacts. The following instruments are used  .2. Screening for the presence of ADHD is performed with the first six items of the Adult ADHD Self-Report Scale (ASRS v1.1) ,28.3. The DSM-IV diagnosis of ADHD is based on a semi-structured interview, the Conners’ Adult ADHD Diagnostic Interview for DSM-IV (CAADID) .4. Screening for the presence of a Borderline Personality Disorder is performed with the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) .5. In case of a score of seven or higher on the MSI-BPD, diagnostic evaluation of a Borderline Personality Disorder is performed with the corresponding module of the Structured Interview for DSM-IV Axis II (SCID II) ,32.The first two instruments were already implemented on the research site because they were used in an international study on the prevalence of ADHD in adults seeking treatment for substance use disorders  , developThe ASRS has been validated for use in the general adult population  and someThe CAADID consists of two parts. In the first part of the CAADID, information is obtained on the developmental history of the patient. This part can be filled out by the patient, preferably with the help of parents, before coming to the diagnostic appointment. In the second part of the CAADID, the presence of all ADHD symptoms is checked for both childhood and adulthood. Although it is generally recommended to include an interview with a family member in the diagnostic procedure in order to obtain information on childhood behaviors, we chose not to include such an interview in our diagnostic procedure. This choice was made because of logistic reasons and also because we encounter a lot of patients who have lost contact with their relatives due to their substance use disorder. Moreover, the study by Murphy and Schachar showed that adult patients can give a true account of both childhood and current symptoms of ADHD . AnotherThe MSI-BPD yielded both good sensitivity (0.81) and good specificity (0.85) in a non-substance abusing population when using a cut-off value of 7 . In case1. The ADHD rating scale is used as the measure for severity of ADHD symptoms , Dutch v2. The Time Line Follow Back (TLFB) -44 is us3. The Beck Depression Inventory (BDI)  is used 4. The EQ-5D is a five-dimensional instrument for measuring quality of life ,48. The 5. The TIC-P is a questionnaire measuring the costs associated with psychiatric illness . It has 6. Computerized neuropsychological tests are performed to objectively assess (changes in) ADHD associated neuropsychological functions.a. The Balloon Analogue Risk Task (BART)  providesa. The Stroop Color-Word task -60 provia. The Tower of London task  is perfo7. Results of urine samples and breath analyses are used to provide additional, objective information on substance use.The primary outcome measure is the difference in the severity of ADHD symptoms according to the ADHD rating scale  between Key secondary outcome measures are the difference in the severity of ADHD symptoms between the two conditions at follow up two months after end of treatment (t2), and the difference of percentage of treatment responders , j = 2,3 as dependent variable vector; treatment condition, time and the treatment condition by time interaction as predictor, and Yt1  as covariate. This model assumes missing at random (MAR), which adjusts the effect estimates for potential bias due to differential loss to follow-up. GLMM will also be used for the analysis of the secondary outcome variables, except the binary treatment responder outcome, for which a Generalized Estimating Equation model (GEE) will be used.Data will be analyzed according to the intention-to-treat principle. The effect of the integrated treatment in terms of the primary outcome variable will be assessed with generalized linear mixed model regression analysis (GLMM) with .The primary outcome is the difference in the severity of ADHD symptoms according to the ADHD rating scale  between http://www.clinicaltrials.gov as NCT01431235.This RCT has been reviewed and approved by the ethics committee of the Academic Medical Centre in Amsterdam (number 10–130). It is registered in To the best of our knowledge, this is the first randomized controlled trial to test the efficacy of an integrated CBT protocol aimed at reducing SUD as well as ADHD symptoms in a SUD population with comorbid adult ADHD. In the absence of effective pharmacological treatment options for ADHD in these patients, it is vital that other treatment options such as CBT are tested. Recent results of CBT interventions in ADHD patients, as shown by Safren et al. , SolantoIn the regular practice of our SUD treatment centre, abstinence of substances is pursued first, and referral to an ADHD outpatient clinic is generally effectuated at a later stage. However, ADHD patients are often not identified in this population whereas ADHD symptoms often interfere with SUD treatment, for example in the most elemental way by forgetting appointments with therapists due to a lack of organization skills. This results in less optimal SUD treatment outcomes and very low numbers of patients actually receiving adequate ADHD treatment. We hypothesize that integrating treatment of ADHD symptoms with SUD treatment will show a better outcome. Two major challenges in both treatment and research of these patients with complex disorders are the tendency to relapse into substance use and the problems with planning and treatment adherence. In fact, we envisage that the greatest challenge of this study will be to prevent participants from dropping out of the study. We expect that SUD patients with comorbid ADHD will show higher levels of impulsivity and treatment drop-out, which requires a creative and persistent approach from both therapists and investigators. We addressed this by giving special attention to the format of the treatment: we chose for an individual version in order to allow for optimal flexibility of patient inflow and to avoid waiting lists. We also try to schedule the appointments in both treatment conditions at a fixed day and time to minimize the chance of forgetting appointments, and patients are reminded of their appointments by text messages sent the day before the appointment. Furthermore, in our power calculation we allowed for relatively high numbers of drop outs in phase 1 of the treatment. Patients who drop out of treatment in phase 2 of the treatment are still approached for outcome and follow up assessments; if patients are unwilling to come to the clinic for this purpose, a shortened version consisting of the ADHD rating scale and the Time Line Follow Back is administered by telephone in order to collect at least the most important data from as much participants as possible. We also expect that relapse into substance use, or inability to become abstinent, will be a common problem in both treatment conditions. Although treatments are aimed at full abstinence, relapse and continued substance use are no reason to end the treatment, but they will require therapists to use the treatment protocol in a flexible way. This can lead to diminished protocol adherence, but on the other hand enhances ecological validity of the study.In this first trial, information is collected on acceptance, feasibility, efficacy and cost-effectiveness of the integrated treatment program compared to TAU only. It should be noted, however, that we adapted the original adult ADHD treatment program of Safren et al. ,23 to a Patients who are already on a stable dose of ADHD medication at study entry, can participate in the study, but new medication is not provided to the participants. As efficacy of stimulants and other ADHD medication has not been shown in randomized trials yet, the efficacy of the current medication options is at least controversial. If patients want to start ADHD medication, they have several options: they can be included in the study if they agree to postpone medication use until the end of study (i.e. after the two months follow-up period) or they can refuse participation in this study and be referred to an ADHD treatment centre where medication can be prescribed. Of course, patients can withdraw from participation any time during the study and therapists can always refer a participant for a medication consult if they feel that medication is necessary.An important difference between the current study and the study by Safren et al.  concernsThe unequal amount of therapy sessions that participants in the integrated treatment condition and in the TAU only condition receive is a limitation as well. Although we are aware that conclusions on the effectiveness of the CBT interventions for ADHD are limited because any effects, should they occur, can be attributed to having had more therapy time and attention in general, we decided in favor of this design as it is the first study on this issue in this patient population. Furthermore, the difference in time spent in therapy between the two conditions is relatively limited and may in reality even be smaller since not all patients will attend all sessions. In this first study we want to explore whether a combination of a little extra time with a more specific ADHD treatment is effective at all and whether this is cost-effective.Another limitation of our design is the fact that assessors are not blinded for treatment allocation (and of course patients and therapists are not blinded either), because of logistic reasons. Again, we realize that this may introduce (information) bias. However, the presence of objective measures such as neuropsychological tests and biological markers of substance use will allow us to explore whether such bias really occurred and how such bias may have influenced the results.Despite these challenges and limitations, we think that this study provides a first important step towards developing a tailored integrated treatment protocol for patients with SUD and comorbid ADHD.The authors declare that they have no competing interest.KvE coordinates data-collection, was involved in preparing the integrated treatment protocol and drafted the research protocol and the current paper. EV was involved in preparing the integrated treatment protocol; supervises the clinical delivery of the treatments, supports the management of the project and critically revised the manuscript. WvdB contributed to the design of the study; supervises the management of the project and critically revised the manuscript. MWK provided statistical expertise to the protocol. KdB contributed to the preparation of the integrated treatment protocol. RAS contributed to the design and organization of the study and obtained funding; supervises the project and critically revised the manuscript. All authors have contributed to the writing of this paper and have read and approved the final paper.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/132/prepub


Bartonella species are increasingly associated with a range of human and animal diseases. Despite this, we have a poor understanding of the ecology and epidemiology of many species, especially those circulating in wild populations. Previous studies have demonstrated that a diverse range of Bartonella species are abundant in wild rodent populations; little is known regarding their modes of transmission, although both direct and indirect routes have been suggested. In this study, with bank voles (Clethrionomys glareolus) as the host species, we demonstrate that the rodent flea Ctenophthalmus nobilis is a competent vector of at least two Bartonella species, B. grahamii, which has previously been associated with human infection, and B. taylorii. In contrast, no evidence of either horizontal or vertical transmission was seen in bank voles inoculated with B. taylorii maintained in an arthropod-free environment; this finding suggests that fleas may be essential for transmitting some Bartonella species. Bartonella currently contains 19 species of gram-negative bacteria that parasitize the erythrocytes of vertebrate hosts, and an increasing number of species are now considered as emerging infections of medical and veterinary importance  of transmission. Bartonella species are generally considered to be transmitted by arthropod vectors, and Bartonella DNA has been detected in fleas and ticks collected from both wild and domestic animals (Lutzomyia verrucarum) for B. bacilliformis (Pediculus humanus) for B. quintana  for B. henselae  was demonstrated to be a competent vector of an unidentified Bartonella species that infected bank voles (Clethrionomys glareolus) (Trombicula microti) was proposed as a vector of B. vinsonii  where previous studies had shown the prevalence of Four weeks after the bank voles were added to the arena, all were euthanized, and blood samples were collected by cardiac puncture. In addition to the 28 voles originally introduced to the arena, one female had produced a litter, and the two pups produced were also humanely killed and had sterile blood samples collected. Fleas were collected from all rodents and kept in individual tubes (1 per rodent) containing 70% ethanol. A sample of fleas from bedding within the arena was collected at the same time. All fleas were identified to species level (Bartonella spp. from the blood samples was undertaken by plating freeze-thawed blood onto Colombia blood agar plates enriched with 5% horse blood. Plates were incubated at 37°C and 5% CO2 for up to 14 days. Isolates putatively resembling Bartonella spp. colonies were further characterized by polymerase chain reaction (PCR). Individual colonies were prepared by boiling in 100 μL of sterile deionized distilled water for 10 min. Five microliters of this preparation were used as template. Each 50-μL reaction contained 1.25 U of Taq polymerase, 200 mM of each dNTP, 1.5 mM of MgCl2, and 30 pmol of each primer. Initial characterization used primers QHVE1 and QHVE3 (HaeIII as previously described (gltA) gene. After purification these PCR products were sequenced with an ABI 377 automated sequencer, and the sequences were compared with previously published sequences by using the BLAST program from the National Center for Biotechnology Information Web site (available from: http:/www.ncbi.nlm.nih.gov/BLAST/).Isolation of 6 CFU of Bartonella taylorii. In two of the cages both voles were inoculated, in two only the male vole was inoculated, and in four others only the female vole was inoculated. Pairs were kept until they had produced a litter. Blood samples were taken at day 0, when the voles were inoculated, at day 10 to confirm infection status of the adults, and 8 weeks later when litters were between 7 and 14 days old. Isolation attempts were carried out as described.Horizontal and vertical transmission experiments were undertaken using 16 bank voles, housed, in the absence of fleas, in cages containing male-female pairs approximately 4 weeks of age, one or both of which was injected through the footpad with approximately 10Bartonella spp., and all of these were confirmed as Bartonella spp. by PCR. Restriction enzyme analysis of the resulting PCR products showed that two different Bartonella genotypes were present in the bank voles (gltA gene showed these to represent B. taylorii (16 isolates) and B. grahamii (6 isolates) (one bank vole was coinfected with both). In addition to the original 28 voles added to the arena, two pups were sampled that had been suckling from a bacteremic female. Neither was bacteremic.Twenty-one of the 28 blood samples from the bank voles produced colonies resembling nk voles . SequencCtenophthalmus nobilis nobilis. Ten pools of five randomly selected fleas collected from the voles were tested for Bartonella spp. DNA using the gltA PCR. All pools tested positive, and of 10 individual fleas collected directly from the arena itself, 7 tested positive for Bartonella spp. DNA. Four were positive for B. taylorii, one for B. grahamii, and two for both.A total of 217 fleas were collected from the 28 bank voles (mean 7.75 fleas per vole). Only one species of flea was identified, None of the naïve adults involved in the horizontal transmission experiment acquired infection directly from its mate, despite that all inoculated animals remained bacteremic throughout the experiment. Seven of the eight pairs of voles produced a litter, one of the pairs in which the female alone was inoculated did not. A total of 20 young were produced from the seven litters, with litter sizes ranging between one and five offspring (mean 2.86 offspring per litter). No bacteremia could be detected in any of the offspring, whether only one or both parents had been inoculated.B. taylorii and 6 voles (21.4%) infected with B. grahamii. Similarly, each of 10 pools of 5 fleas collected showed the presence of Bartonella spp. DNA within them, and 7 of 10 individual fleas were also positive. Fleas have previously been implicated in the transmission of B. henselae infections of cats  naïve bank voles housed with wild-caught fleas for 4 weeks became bacteremic, 16 voles (57.1%) infected with B. henselae (Bartonella could be isolated from the neonates and embryos of naturally infected North American rodents, while transplacental transmission of B. birtlesii was also reported in BALB/c mice, although none of the viable offspring in that study were bacteremic (On the other hand, no transmission occurred between infected and susceptible animals when housed together in the same cage in the absence of fleas, and no transmission could be detected from parent to offspring, although larger numbers of animals may be needed to confirm that such transmission does not occur. This absence of vertical transmission agrees with results of a study of cats infected with B. grahamii has previously been associated with human disease (B. taylorii is as yet unknown. Furthermore, the implication of fleas in the transmission of these rodent Bartonella, as well as B. henselae (Bartonella species, some of which have already been shown to be pathogenic to humans. Whether the route of rodent to human transmission is likely to be due to flea transmission or through direct contact, such as bites or scratches as is commonly the case for B. henselae (These findings are of potential public health importance: Bartonella to susceptible rodents remains unclear. Future work should seek to distinguish the role of fecal contamination and then the role of scratching (Bartonella species would be valuable as would determining whether fleas infected with a number of Bartonella species transmit one species more efficiently than the others. Studies such as these would help expand the current knowledge on vector-Bartonella specificity and determine its importance in influencing the diversity of Bartonella species.The exact route by which fleas transmitted


Attention Deficit Hyperactivity Disorder (ADHD) is often comorbid with psychiatric and developmental disorders. This study aimed to investigate the prevalence of obesity and overweight among Chinese children with ADHD, and to explore which subtypes of the disorder may specifically be associated with obesity/overweight.Children meeting the DSM-IV criteria for ADHD were enrolled in the study. Weight, weight z-score, height, height z-score, BMI, and BMI z-score were used to evaluate growth status. Obesity and overweight were determined using the National Growth Reference for Chinese Children and Adolescents. Relations between the prevalence of obesity/overweight and different ADHD subtypes and pubertal development were analyzed.A total of 158 children with ADHD (mean age: 9.2 years) were recruited for the study. The prevalences of obesity, overweight, and combined obesity/overweight were 12.0%, 17.1%, and 29.1%, respectively, which were significantly higher than in the general Chinese population . Multivariable analysis showed that the children with the combined subtype of ADHD and the onset of puberty were at a higher risk of becoming obese or overweight.The prevalence of obesity in Chinese children with ADHD is higher than that of the general population. Children with the ADHD combined subtype who were at the onset of puberty were more likely to be overweight or obese. Attention deficit hyperactivity disorder (ADHD) is recognized as one of the most common childhood psychiatric disorders, and is characterized by age-inappropriate inattention, hyperactivity-impulsivity, or both ,2.The coIn recent years, ADHD was found to be linked with another increasing worldwide childhood disorder: obesity -15. The Although many studies suggest a potential comorbidity between obesity and ADHD, other results have shown that the rates of overweight and obesity among children with ADHD were not higher than the rates in the general population ,21. HoweTaking this research into consideration, the present study was performed in Zhejiang Province, China. We hypothesized that the prevalence of obesity was higher in ADHD patients, and that a specific subtype of ADHD was associated with obesity. Our aims were as follows: 1) to investigate the prevalence of obesity or overweight among Chinese children with ADHD, and to compare this prevalence with what is reported in the general Chinese population, and 2) to analyze the prevalence of obesity/overweight in children with different subtypes of ADHD to identify which dimension(s) of ADHD may specifically be associated with obesity/overweight.The data for this study were collected from outpatients who were believed to be affected by ADHD on their first visit to our clinic between March 1, 2010 and August 31, 2010. Patients visited this clinic only for psychological problems. No children who simply displayed obesity or overweight visited the clinic. The hospital has a separate center for the diagnosis and treatment of children with obesity and overweight. Therefore, sampling bias was avoided in this study. Participants who were diagnosed with any subtype of ADHD [Subjects with ADHD were eligible to participate in the study at our clinic at the Children’s Hospital, Zhejiang University School of Medicine, which specializes in evaluating and treating children with behavioral, developmental, and psychiatric disorders. The children underwent a comprehensive assessment process by a trained multidisciplinary ADHD diagnostic team, including physical examination, EEG, ECG, Vanderbilt ADHD Diagnostic Parent and Teacher Rating Scales, Conners’ Parent and Teacher Rating Scales (Chinese version), SNAP-IV, and Wechsler Intelligence Scale for Chinese Children (WISC-R) . The chiChildren included in this study met the following criteria: (a) diagnosed with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)  criteriaIndividuals were excluded if they had: (a) a psychiatric diagnosis with significant symptoms  and mental retardation; (b) sensorimotor handicaps ; (c) taken drugs such as methylphenidate in any form, clonidine, or atomoxetine for controlling ADHD symptoms; or (d) serious somatic disorders, such as cardiovascular diseases, hyperthyroidism, serious gastrointestinal stenosis, dysphagia, exogenous steroid hormones, and sexual development disorders.Growth data were taken during the first recruitment visit by one assistant. Body weight was measured to the nearest 0.10 kg while the subjects were wearing lightweight clothing, and height was measured to the nearest 0.10 cm without shoes and hats.The indicators of weight percentile, weight z-score, height percentiles, height z-score, BMI percentiles, and BMI z-score were used to determine the individuals’ growth, which was evaluated using the National Growth Reference for Chinese Children and Adolescents . Individth and 95th BMI percentiles.We referenced the growth chart for Chinese children and adolescents aged 0–18 years as the standardized tool to define normal weight, overweight, and obesity ,27. ThisTo assess the stage of pubertal development, children older than 8 years were asked questions about pubertal development. These included questions about the presence or absence of pubic hair, axillary hair, facial hair, and nocturnal emission for males; and pubic hair, axillary hair, and menses for females; as well as the age of attainment of each stage. Based on these questions, estimates of the individuals’ pubertal developmental stages were defined as follows: absence of pubic hair and any other sign of puberty was the pre-pubertal stage; attainment of any sign of puberty was the pubertal stage.t-test was used to compare the z-scores of height, weight, and BMI to the mean value of 0, the normal distributions of the sample values were tested. Differing gender and pubertal developmental stages were both categorical data, and were analyzed by chi-square analysis or Fisher’s Exact Test, for any analysis with a count in a cell of fewer than 5. A P value of less than 0.05 was regarded as statistically significant for all statistical tests. Three categories of independent variables considered to be associated with the prevalence of obesity/overweight were examined: (1) gender, (2) pubertal developmental stage, and (3) subtypes of ADHD. We used univariate analysis to quantify the association between variables and obesity. Variables found to be statistically significant in univariate analysis were used to establish a multivariable logistic regression model with a forward stepwise method to determine the risk factors for obesity.Data were entered into Excel software and analyzed in the SPSS (version 13.0) software package. Before a one-sample There were 162 children diagnosed with ADHD between March 1, 2010 and August 31, 2010. Four children were excluded from the study because either their consents were not obtained, or the information they provided was incomplete. The characteristics of the subjects are summarized in Table The prevalences of obesity, overweight, and combined obesity/overweight were 12.0% (19/158), 17.1% (27/158), and 29.1% (46/158), respectively, in this group of children with ADHD. The prevalence depended on the pubertal developmental stage and ADHD subtype (Table th percentile was 8.23% (13/158).Anthropometric data of the study samples, including the distribution of height and BMI in percentile, are presented in Table Univariate analysis showed that three potential risk factors were associated with obesity/overweight. Children in the pubertal stage were more likely to be overweight/obese . Children with ADHD combined subtype had a greater possibility of being overweight/obese . Gender was not a risk factor for obesity/overweight.Multivariate analysis Table  demonstrIn the present study, we found that the prevalence of obesity/overweight in Chinese children in Zhejiang Province with ADHD is 29.1%, which is higher than the figure of 6.6% found in the national survey of the normal population in 2002 . When weHere, we want to emphasize several strengths of this study. First, our study was conducted in children who were diagnosed with ADHD for the first time and who were medication-naive, which minimized the potential influence of drugs on growth status ,40. SecoSeveral hypotheses ,42 have Interestingly, this study found that pubertal development was associated with a higher prevalence of obesity/overweight in children with ADHD. When the sample of the ADHD group was restricted, children in puberty were associated with a four-fold increase in the odds ratio of obesity/overweight compared with those in the pre-pubertal stage. van Egmond-Frohlich and colleagues  found thth percentile was 8.23% (13/158), suggesting that the prevalence of underweight was also higher in the ADHD group. Most of them were males (12/13) who were diagnosed with ADHD inattentive type (8/13), followed by ADHD hyperactive-impulsive type (3/13), and ADHD combined type (2/13). This result was first reported in a retrospective survey with only three cases [Another interesting finding was that the proportion of children with BMI below the 5ee cases  that shoThe potential limitations of this study should be taken into consideration. First, the cross-sectional design precludes determining any causal inferences in the relationship between ADHD and obesity. Second, no control group was set to compare with the study group. However, in addition to comparing our results with the national survey, other investigations in China were used for comparison, including one conducted in Zhejiang Province, which could produce relatively objective conclusions. It should also be taken into consideration that the prevalence of obesity is rising quickly, and the data may not be completely up to date. Third, demographic and family information, obesity family history, and other parental characteristics of the ADHD group were not collected, and our population may have different lifestyles, food sources, and general structure, which would affect the children’s nutritional status. Finally, pubertal stages were estimated based on self-report, and data on the variety of pubertal stages were not collected, which might produce bias and affect the results. Therefore, a scientific design using a multi-center and random sampling method with larger sample size could be used to better explore this comorbidity.Our findings demonstrated that the prevalence of obesity in children with ADHD was higher than in the general population, which strongly supports obesity as another comorbidity of ADHD in Chinese children. Children with ADHD of the combined subtype and in puberty had a higher risk for obesity/overweight. These findings extend the comorbidity of ADHD and obesity to Chinese populations, consistent with previous findings reported in other populations.The authors declare that they have no competing interests.RY and ZZ were responsible for the conception and design of the study. RY and SM performed the data analysis. All authors participated in interpretation of the findings. RY and SZ drafted the manuscript. RL and ZZ revised and commented on the draft and all authors read and approved the final version of the paper.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/133/prepub


Rye products have been demonstrated to lower the acute insulin demand, induce a low and prolonged blood glucose response  and reduce subclinical inflammation. These products may therefore contribute to a lowered risk of obesity, type 2 diabetes and cardio vascular disease. The objective of the present paper was to evaluate the mechanism for a reduced postprandial insulin demand with rye products, and to explore possible appetite regulating properties.2), and subjective satiety was evaluated during the postprandial phase. 270 min after the breakfast, an ad lib lunch buffet was served and the voluntary energy intake (EI) was registered.10 healthy subjects were served breakfast meals (50 g of available starch) with endosperm- or whole grain rye breads, with and without lactic acid, boiled whole grain rye- (RK) or wheat (WK) kernels, or white wheat bread reference (WWB) in random order in a cross-over design. Plasma concentrations of glucose, ghrelin, serum insulin, free fatty acids, adiponectin, breath hydrogen excretion (Hdesire to eat before lunch (AUC 210-270) and to a lower concentration of ghrelin in the late postprandial phase after breakfast (270 min), r = -0.29 and -0.29), which in turn was related to a lower voluntary EI (r = 0.43 and 0.33). The RK breakfast improved satiety in the early postprandial phase (0-60 min) compared to WWB, and induced a lower EI at lunch (-16%). A high content of indigestible carbohydrates in the breakfast products was related to improved satiety , and a higher breath H2 in the late postprandial phase . High H2 (AUC 120-270 min) also correlated with lower EI (r = -0.34).All rye products and WK induced lower insulinemic indices (II) than WWB. A lower incremental insulin peak following breakfast correlated with a lower EI at lunch (r = 0.38). A low II was related to improved satiety in the early postprandial phase . RK induced a higher GP compared to WWB and WK. A higher GP was related to a lowered Rye products, rich in indigestible carbohydrates, induce colonic fermentation already post the breakfast meal, and lowers acute insulin responses. A high excretion of breath H2 also correlated with a higher GP. Especially, rye kernels induced a high GP which was associated with a 16% lowering of energy intake at a subsequent lunch meal. The bulking effect of rye fiber, colonically derived fermentation metabolites, a high GP and a low insulin response possibly all contributes to the benefits on glucose- and appetite regulation seen in an acute and semi-acute perspective. Secale cereale) have previously been shown to induce a low insulin response [The prevalence of obesity and type 2 diabetes (T2D) is increasing globally and preventive strategies are urgently needed. Whole grain foods have been shown to facilitate weight regulation and to lower the risk of T2D, cardio vascular disease (CVD) and the metabolic syndrome -8. The presponse -18 whichresponse . FurtherAvoidance of frequent and elevated blood glucose excursions is protective against oxidative stress and subclinical inflammation . FurtherSince rye bread products are frequently processed using sour-dough fermentation, the potential effect of organic acids also deserve attention in this context. Lactic acid addition to bread has previously been reported to lower glycemic response .ad libitum buffet lunch meal was served and the energy intake was registered.In the present study, the metabolic and appetite regulating properties of rye breads made from endosperm or wholegrain rye flour, were investigated in healthy subjects, using white wheat bread as reference (WWB). The effect of adding lactic acid to the rye breads was also studied. In addition, test products made by boiling of kernels from rye and wheat, respectively, were included. The test products were provided as breakfasts and postprandial plasma were analyzed for measures of glucose metabolism , and appetite regulating hormones (ghrelin). Additionally markers of colonic fermentation were measured (breath hydrogen excretion). Finally, subjective satiety was evaluated in the postprandial phase. At 270 min after the breakfast, an 2) and without drug therapy participated in the study. All subjects had normal fasting plasma glucose concentrations (5.5 ± 0.1 mmol/L). The subjects were recruited in March 2007 and the study was performed from April to June 2007. All subjects gave their informed consent and were aware of the possibility of withdrawing from the study at any time they desired. Approval of the study was obtained from the regional ethical review board in Lund, Sweden (reference number 109/2007)Ten healthy non-smoking volunteers (5 men and 5 women) aged 26.0 ± 1.1 y with normal body mass indices  were provided by Lantmännen R&D . Commercial white wheat flour was obtained from Kungsörnen AB . Whole wheat kernels (Tiger) were provided by BFEL (Germany). Dry yeast was obtained from Jästbolaget AB  and lactic acid (88-92% extra pur) from Riedel-de Haën .The white wheat bread (WWB) was made from 540 g of white wheat flour, 360 g water, 4.8 g dry yeast, 4.8 g NaCl and baked in a bread baking machine  using a program for white bread.Endosperm rye bread (ERB) was made from 5000 g endosperm rye flour, 3413 g water, 84 g dry yeast and 43 g NaCl (containing 5 mg KI/100 g). The dough was mixed for 8 minutes and proofed at room temperature for 30 minutes. It was divided into pieces of 1000 g each and placed in baking tins. The dough was subjected to a second proofing  during 30 minutes for the endosperm rye breads and 45 minutes for the whole grain rye breads. Baking was performed initially at 250°C with 3 sec of steam. The temperature was then immediately lowered to 200°C and the breads were baked for 40 min.Endosperm rye bread with lactic acid (ERB-lac) was made from 5000 g endosperm rye flour, 3322 g water, 90 g lactic acid, 84 g dry yeast and 43 g NaCl (containing 5 mg KI/100 g). The bread was made using the same method as for ERB.Whole grain rye bread (WGRB) was made from 5000 g coarse whole grain rye flour, 3661 g water, 84 g dry yeast and 43 g NaCl (containing 5 mg KI/100 g). The bread was made using the same method as for ERB but was baked for 45 min.Whole grain rye bread with lactic acid (WGRB-lac) was made from 5000 g coarse whole grain rye flour rye flour, 3574 g water, 90 g lactic acid, 84 g dry yeast and 43 g NaCl (containing 5 mg KI/100 g). The bread was made using the same method as for WGRB.The WWB was left to cool for 1 hour and the rye breads for 21 hours under cover. Thereafter, the crust was removed and the breads were sliced and wrapped in aluminum foil in portions sizes, put into plastic bags and stored in a freezer (-20°C) until use. The day before the experiment, the breads were taken from the freezer and were thawed over night at ambient temperature, still wrapped in aluminum foil and in the plastic bag.The wholegrain wheat kernels (WK) and rye kernels (RK) were prepared on the day of the experiment. 97.1 g of whole wheat kernels and 0.5 g NaCl were boiled in 156.4 g water for 40 minutes. 106.6 g whole rye kernels and 0.5 g NaCl were boiled in 189.5 g water for 35 minutes. All water was absorbed by the kernels.ad libitum lunch buffet was served at 270 min after breakfast to measure voluntary food intake. The buffet meal was a common Swedish lunch meal and was composed of meatballs , pasta , ketchup  and cucumbers. The cucumbers were fresh, and were peeled and sliced prior to serving to ensure homogeneity. Meatballs (240 g) were heated in a microwave oven  for 4 min at 850 W. The pasta (325 g dry weight) was boiled for 8 min in 3 liters of water with 2 teaspoons (13 g) NaCl. One tablespoon of rapeseed oil  was added to the pasta after boiling.An Prior to analysis of the total starch, fiber and protein content, the breakfast products were air dried and milled . Measurements of resistant starch (RS) was performed on products as is. Total and resistant starch was analyzed according to Björck et al.  and ÅkerThe test and reference products were provided as breakfasts, on 7 different occasions, in random order separated by approximately 1 wk. The subjects were instructed to eat a standardized evening meal (9:00-10:00 P.M) prior to the test, consisting of a few slices of white wheat bread. No eating or drinking except for small amounts of water was then allowed until the start of the test. The subjects were also told to avoid alcohol and excessive physical exercise the day before each test, and otherwise as far possible maintain their regular life style throughout the entire study. The subjects arrived at the laboratory at 07.45 a.m. on the test day. A peripheral venous catheter  was inserted into an antecubital vein.Fasting blood samples were taken prior to the breakfast meal at time 0. Thereafter the test meals, contributing with 50 g of available starch, were served with 250 ml of tap water. The test subjects finished the breads within 14 minutes and the kernels within 25 minutes. At 120 min after the breakfast, the test subjects were served 250 ml of tea, coffee or water without any sweeteners or milk products. The chosen beverage remained consistent for each individual at all 7 visits.At 270 min after commencing the breakfast meals, the subjects were provided the lunch buffet and were instructed to eat the amount needed to reach comfortable satiation. At the following visits they should eat until they reached the same degree of satiation as on their first occasion. On their first visit, the subjects could drink as much water as they desired, and the same amount of water was then served at the following 6 visits. The subjects had to finish their lunch within 30 min, before the next blood sampling occasion at 300 min after commencing breakfast. The weight of the different food items ingested was registered individually to allow calculation of the energy intake at the buffet lunch meal. The energy content of the foods in the lunch buffet was obtained from the manufacturer of the products, and that of the cucumber from food tables .2) was measured as a marker of colonic fermentation, using an EC 60 gastrolyzer . In addition, the subjects were asked to fill in their subjective feeling of fullness, hunger and desire to eat, respectively, using a 100 mm Visual Analogue Scale (VAS).Capillary blood samples were taken for analysis of plasma glucose (p-glucose). Venous blood samples were drawn for the analysis of serum insulin, serum free fatty acids (s-FFA), s-adiponectin and p-ghrelin. Breath hydrogen excretion  tubes were left in ice bath for approximately 1 h before being centrifuged for 11 min . Serum and plasma were thereafter immediately separated and the samples were frozen at -20°C (serum) or -40°C (plasma) until analysis. Plasma for ghrelin analysis was sampled into tubes containing 500 KIU aprotinin  per ml of whole blood.Glucose was analyzed using a p-glucose analyzer . The s-insulin analysis was performed on an integrated immunoassay analyzer  using an enzyme immunoassay kit . S-FFA were analyzed using an enzymatic colometric method . S-adiponectin was analyzed using an enzyme immunoassay kit , and p-ghrelin with a radioimmunoassay kit .One subject was excluded from the analysis of data from the WGRB breakfast due to having a cold at that particular test day. The data for WGRB is therefore analyzed with n = 9. Data are expressed as means ± SEM.The total area under curve (AUC) was calculated for each subject and test meal, using the trapezoid model. The glycemic index (GI) is defined as the incremental positive area under the blood glucose curve after a test product, expressed as a percentage of the corresponding area after an equi-carbohydrate reference product taken by the same subject . The insThe glycemic profile (GP) defined as the duration of the glucose curve divided with the incremental glucose peak was calculated , with thHydrolysis index were calculated from the 180 min AUC for in vitro starch hydrolysis, in a similar way of calculating GI and II values, using WWB as a reference .Time x treatment interactions for glucose, insulin, ghrelin, satiety, breath hydrogen, FFA and adiponectin responses were analyzed using a mixed model  with repeated measures and an autoregressive covariance structure. Subjects were modeled as a random variable and corresponding baseline  value were modeled as covariate. The data were analyzed using a mixed model analysis of covariance (ANCOVA) with subject as a random variable and corresponding baseline  as a covariate. For voluntary energy intake at lunch and HI, a mixed model analysis of variance (ANOVA) was used with subject as a random variable. Differences between groups were identified using Tukey's multiple comparison tests. . In the cases of unevenly distributed residuals (tested with Anderson-Darling test), Box Cox transformation were performed on the data prior to the ANCOVA and ANOVA. Correlation analysis was conducted to evaluate the relation among dependent measures with the use of Spearman's partial correlation coefficients controlling for subjects and corresponding baseline values (two-tailed test), . p < 0.05 was considered statistically significant.The rye products and WK displayed a lower rate of starch hydrolysis, expressed as HI, than did WWB Table . Further-1·L-1) was higher for RK than for WWB and WK. Generally, rye products induced higher GP's than wheat products (mean GP 74 for rye and 50 for wheat) No time x treatment interaction was found (0-270 min).All products except the ERB displayed lower glycemic indices (GI's) than WWB, with GI's ranging from 64 to 79 Table . WK and All breakfast products induced lower insulinemic indices than WWB ranging from 60 for the kernel based products to 75 for the whole grain rye bread Table . In the 2 excretion than WWB . Furthermore, RK, WGRB and WGRB-lac generated higher H2 than ERB-lac following the buffet lunch (AUC 270-390 min)Prior to lunch, RK induced higher H2 were observed at specific time points . At 240 min, WGRB induced higher H2 excretion than WWB and ERB and at 270 min; RK and WGRB induced higher H2 excretion than WWB and ERB-lac. No significant time x treatment interaction was found for the interval 270-390 min.Significant differences in Hfeeling of fullness and all but ERB-Lac, WGRB-lac and WGRB induced less desire to eat than WWB in the early postprandial phase after breakfast . Furthermore, WGRB-lac and ERB-lac induced higher feeling of hunger than RK breakfast in this interval. In the later postprandial phase (120-210 min), the test subjects felt hungrier and had a larger desire to eat following the WWB and WGRB breakfasts compared to following the RK breakfast. Furthermore, ERB-lac and WK caused a larger desire to eat compared to RK in this phase. In the hour prior to lunch (210-270 min), hunger was higher following all test products but ERB and WK compared to after the RK breakfast while desire to eat was higher for all breakfast, compared to after RK.feeling of fullness, hunger or desire to eat after the ad lib lunch following the breakfast meals (AUC 300-390), indicating that subjects succeeded in eating to the same degree of satiation, as was intended in the experimental design. No time x treatment effect was found for feeling of fullness, feeling of hunger or desire to eat in the intervals 0-270 or 300-390.There were no differences in To reach the same degree of satiation, subjects decreased their energy intake (EI) at lunch after the RK breakfast compared with the corresponding intake after the WWB breakfast with 16% Figure . Also thFor ghrelin, WGRB-lac induced lower ghrelin AUC in the postprandial period 120-270 min compared to WK. No differences were found between AUC following the different products, in the interval 270-390 min. No time x treatment interaction was found in the interval 0-270 or 270-390 min. Figure .RK induced lower concentrations of FFA than WWB in the later postprandial phase , no change over time, and no time x treatment interaction was found. Nor was there any difference in AUC 0-270 min or 180-270 min between the products Figure .Tables feeling of fullness, lower feeling of hunger and lower desire to eat the first 60 min after breakfast. A high GP was related to a lower desire to eat, both in the early and late postprandial phase (0-60 and 210-270 min). Low late desire to eat (AUC 210-270 min) was also related to a lower EI at the subsequent lunch. A high GP was related to a lower concentration of ghrelin prior to lunch (270 min), in turn correlated with a lower EI. Furthermore, a higher content of indigestible carbohydrates, as well as high water content and larger portion sizes correlated with increased feeling of fullness and a lowered feeling of hunger and desire to eat (0-60 min) as well as lowered EI at lunch. High content of indigestible carbohydrates correlated with a high H2 excretion (120-270 min), which, in turn, was related to a lower EI at lunch. A high H2 excretion (90-270 min) correlated to a higher GP. GP and GI did not correlate. HI for the rye breads was not related to GI, II or GP.Correlations between appetite ratings, physiological parameters and product properties are presented in In the present study, we confirm previous findings of a low insulin response and a high Glycemic Profile following rye products. Furthermore, we demonstrate that rye products beneficially affect both early and late appetite regulation, making them an interesting food component in weight management. The RK breakfast, in particular, improved appetite regulation and increased satiety acutely and at a subsequent meal, as judged from a lower energy intake. Consequently, compared with WWB, RK induced improved satiety ratings in the early postprandial phase after breakfast, and substantially lowered the voluntary energy intake (-16%) at a subsequent lunch. As a result of this the cumulative energy intake (breakfast + lunch) was lower on the RK day compared to the WWB test day.Part of the early satiating effect of RK may be explained by portion size. Despite being similar to the other test products regarding energy content, the RK breakfast had the largest volume of the test products. The difference in size of the test products can be explained by the fact that RK was the test product containing the highest amount of indigestible carbohydrates (dietary fiber + resistant starch), contributing to a higher water-binding capacity during processing (cooking). Improved early (0-60 min) satiety ratings after the test meals correlated well with a high content of ingestible carbohydrates, a large portion size and a high water content in the products. The satiating effect of bulk-inducing indigestible carbohydrates and water has previously been demonstrated by Rolls et al.  who show2 has been shown to be a sensitive indicator of increased carbohydrate fermentation in colon [2 prior to lunch (120-270 min) was related to a following lowered voluntary energy. Rye products tended to increase breath H2 prior to lunch, significantly so following the RK and WGRB breakfasts. After lunch, all rye products except the ERB-lac induced higher H2 excretions than WWB. All rye products had a high content of soluble fibers, probably explaining the early fermentation. Colonic fermentation of indigestible carbohydrates yields SCFA [A low voluntary energy intake at lunch could be explained by increased colonic fermentation; Breath Hin colon  and a hilds SCFA , which mlds SCFA . In supplds SCFA  has demolds SCFA  demonstrper se that affect satiety. A slow uptake of carbohydrates would lead to a prolonged exposure of the small intestine to nutrients, thus extending the release of satiety peptides, e.g. GLP-1 [desire to eat both in the early and late postprandial phase (AUC 0-60 and 210-270 min). Furthermore, a lower concentration of ghrelin and a lower Desire to eat was related to a lower voluntary energy intake.Improved satiety ratings in the early postprandial phase after breakfast and a lowered voluntary energy intake at lunch were also associated with a low insulin response  following the breakfast test meals. All rye products and the WK were characterized by a lower II than WWB. In a review by de Graaf et al. , insuling. GLP-1 -44. Intag. GLP-1 . In the Rye products were characterized by higher GP than wheat products. Looking at specific rye products, RK induced significantly higher GP than WWB and WK. This is in line with our previous findings . In the ad libitum meal. These findings indicate that the GP represent a nutritionally interesting entity in that it predicts metabolic responses as well as the satiating properties better than does the GI. This work provides information of a potential role in weight management for rye products. A high intake of rye products could contribute to a lowered energy intake, and thus protect against obesity. To evaluate this hypothesis, longer-term studies of rye products on metabolism and appetite regulation are needed.Rye products, especially in the form of whole kernels, decrease both early and late appetite ratings after a breakfast meal, and lowers energy intake at a subsequent voluntary lunch. Our results suggest that a high content of indigestible carbohydrates and soluble fibers in the rye products may beneficially affect acute satiety through a bulking effect, and second meal satiety through a mechanism related to colonic fermentation by production of fermentation metabolites. Colonic fermentation might also contribute to an improved late glucose regulation. Indications of such a hypothesis stems from the correlation between a high breath hydrogen excretion and a high GP. A high GP was also related to lowered insulin response, late postprandial ghrelin secretion and desire to eat, thereby affecting a subsequent 2, breath hydrogen; HI: hydrolysis index; II: insulinemic index; RK: Rye kernels; T2D: type 2 diabetes; WGRB: whole grain rye bread; WGRB-lac: whole grain rye bread made with lactic acid; WK: wheat kernels; WWB: white (endosperm) wheat bread.AUC: total area under the curve; BMI, body mass index; CVD: cardiovascular diseases; EI: voluntary energy intake at lunch; ERB-lac: endosperm rye bread made with lactic acid; ERB: endosperm rye bread; FFA: free fatty acids; GI: glycemic index; GP: Glycemic profile; HThe authors declare that they have no competing interests.LAHR coordinated the study and was responsible for the study design, the collection and analysis of the data, statistical analysis and for writing the paper. EMÖ was involved in the study design, interpretation of data and in writing the paper. IMEB was the guarantor and was involved in the study design, interpretation of data and writing of the paper. All authors have read and approved the final manuscript.


Attention deficit hyperactivity disorder (ADHD) is understood as a developmental disorder which shares common characteristics between childhood, adolescence and adulthood. However, ADHD is widely associated with misconceptions and misbeliefs which can lead to stigmatization. Teachers have an important role for the individual development as they accompany students for a long period of time. The aim of the present study was to explore stigmatizing attitudes in teachers towards adults with ADHD, thereby focusing on the developmental trajectory of the condition. Furthermore, it was aimed to identify factors contributing to prevention and intervention of stigmatization in ADHD.Stigma responses of 170 teachers and 170 comparison participants were measured and compared with a recently developed tool for the assessment of stigmatization towards adults with ADHD. Furthermore, the contribution of knowledge about ADHD and the frequency of contact with adults with ADHD to stigmatization were explored.Reliability and Social Functioning, Malingering and Misuse of Medication and the total scale. With regard to teachers, frequency of contact with adults with ADHD was not related to stigma. However, knowledge about the disorder was negatively correlated with stigma in teachers, indicating lower expressed stigma with increasing knowledge about adult ADHD.Teachers showed significantly less stigmatizing attitudes than comparison participants in various dimensions, including Teachers demonstrated more sensitized attitudes towards stigma in adults with ADHD than comparison participants. Since the present results indicate that knowledge about ADHD increase the sensitivity towards the disorder, special education programs for the community may have the potential to reduce stigmatization towards adults with ADHD. Possibilities for intervention strategies of stigmatization in educational settings were discussed. The association of a group of people with unfavorable, negative beliefs can be described as stigmatization. In this context, it is not relevant whether the assumption underlying these associations is correct or wrong. Research on stigmatization demonstrated that not only physical deviances can set individuals apart and trigger stigmatization but also intrinsic characteristics of the individual such as behavioral deviances have also been found to provoke stigma  in both teachers and education students  = 1.804, p = .179) and educational level (t(338) = 0.974, p = .331).A total of 170 teachers and 170 comparison participants took part in the study and completed the disease specific questionnaire on stigmatization towards adults with ADHD. All teachers were recruited from local secondary schools in Germany. The teachers’ age ranged from 24 to 64 years with a mean age of 43.0 years (SD = 12.4 years). The sample of teachers consisted of 112 (65.9%) female and 58 (34.1%) male participants. All teachers achieved a university degree and completed an applied training in school education. Mean education of teachers was 19.0 years (SD = 2.5 years). Comparison participants were recruited via public announcements, word-of-mouth and through contacts of the researchers involved in Germany. The sample’s age ranged from 22 to 65 years with a mean age of 42.7 years (SD = 13.9 years). The comparison group consisted of 100 (58.8%) female and 70 (41.2%) male participants. Corresponding to the sample of teachers, all participants in the comparison group achieved a university degree with a mean education of 18.6 years in total (SD = 3.8 years). Comparison participants had a variety of professions. However, none of the comparison participants completed a study program for teachers or completed an applied training in school education and none of the comparison participants was currently working in the educational setting in a teaching position. Teachers and comparison participants did not differ in age (t(338) = 0.185, p = .853), gender , exploratory factor analysis (EFA) suggested a 6-factor structure in a principal component analysis (PCA). The use of a PCA was justified by adequate sample size (KMO = .86) and by sufficient large correlations between the items indicated by Bartlett’s test of sphericity (χ2(2016) = 8258.3, p < .001). The scale demonstrated adequate internal consistency (Cronbach’s α = .91) with internal consistencies of the six subscales ranging from .61 to .87. In a second sample (n2 = 517), confirmatory factor analysis (CFA) confirmed the proposed 6-factor model with satisfying model fit (χ2 (614) = 1763.68; p < .01; χ2/df = 2.87; RMSEA = .06; 90%-CI for RMSEA = ; SRMR = .07; CFI = .93). The questionnaire yields a total stigma score and the six subscales Reliability and Social Functioning, Malingering and Misuse of Medication, Ability to Take Responsibility, Norm-violating and Externalizing Behavior, Consequences of Diagnostic Disclosure and Etiology. The six subscales and included items are presented in Table As reported in a previous study  affiliated to the University of Groningen, the Netherlands.2, Cohen’s d) were calculated for all comparisons. As described by Cohen  to an η2 = .0588 and a large effect size (f = .40) to an η2 = .1379. For pairwise comparisons of means, negligible effects (d < 0.20), small effects (d = 0.20), medium effects (d = 0.50) and large effects (d = 0.80) were distinguished . Effect sizes  for teachers and -1.08 (SD = 0.65) for comparison participants. Teachers showed highest stigma responses on subscale 5, followed by subscale 4, subscale 3, subscale 6 and subscale 1, with the lowest observed stigma score on subscale 2. Comparison participants showed a very similar pattern of stigmatization compared to teachers, with highest stigma scores on subscale 5, followed by subscale 4, subscale 1, subscale 3, subscale 6 and subscale . Teachers expressed significant lower stigma than comparison participants on the total scale  = 4.35, p = .038, d = 0.23). For pairwise group comparisons of stigma scores on the six subscales, a Bonferroni adjusted significance level of α = .0083 was applied because of multiple comparisons. Teachers revealed significant lower stigma scores than comparison participants on the two subscales Reliability and Social Functioning  = 12.90, p < .001, d = 0.39) and Malingering and Misuse of Medication F = 16.34, p < .001, d = 0.43). Effects were of small size. Group comparisons with regard to the other subscales revealed only non-significant differences of negligible size  = 1.17, p = .281, d = 0.12; Norm-violating and Externalizing Behavior: F = 3.11, p = .079, d = 0.19; Consequences of Diagnostic Disclosure: F = 0.02, p = .902, d < 0.01; Etiology: F = 0.44, p = .509, d = 0.07). Stigma scores of teachers and comparison participants are presented in Figure Multivariate analysis of variance (MANOVA) revealed a significant small difference of stigmatization between teachers and comparison participants  = 5.604, p < .001, ηThe contribution of self-rated knowledge about ADHD and frequency of contact with adults with ADHD on stigma responses were examined by applying exploratory correlation analyses. Knowledge about ADHD was rated on a scale from 0 (no knowledge) to 10 (expert knowledge) and resulted in a mean score of 4.16 (SD = 1.96) for teachers and 3.77 (SD = 2.25) for comparison participants. Frequency of contact with adults with ADHD was rated on a scale from 0 (never) to 5  and resulted in mean score of 1.56 (SD = 1.41) for teachers and 1.39 (SD = 1.42) for comparison participants. Differences between teachers and comparison participants were non-significant and of negligible size for both knowledge about ADHD (t (311) = 1.443, p = .150, d = 0.18) and frequency of contact with adults with ADHD (t (306) = 1.042, p = .298; d = 0.12).With regard to teachers, significant negative correlations were found between knowledge about ADHD and stigma scores on the total scale , on subscale 1  and on subscale 3 . Associations were of small to medium size. Non-significant negligible to small correlations were found between self-rated knowledge and stigma responses on subscale 2 , subscale 4 , subscale 5  and subscale 6 . Moreover, with regard to the group of teachers, no significant correlations were obtained between frequency of contact with adults with ADHD and stigma responses  and on subscale 4 . The remaining subscales of the stigma questionnaire did not correlate significantly with knowledge about ADHD . Furthermore, the observed correlations were of small size. Significant negative correlations were found for comparison participants between frequency of contact with adults with ADHD and stigma responses on subscale 1 , on subscale 2 , on subscale 3 , on subscale 6  and on the total scale . Correlations were of small to medium size. The remaining subscales  did not correlate significantly with frequency of contact. The observed correlations were of negligible to small size  resulted in a significant lower total stigma score for teachers . Furthermore, these group differences support the sensitivity of the questionnaire in measuring stigma towards adults with ADHD and thereby underline the usefulness of the stigma questionnaire for future research.Comparison of stigma responses between teachers and comparison participants revealed significantly lower stigmatization of teachers on dimensions of To measure the teachers’ personal experiences with adult ADHD, participants were asked to quantify the frequency of contact with an adult suffering from ADHD on a scale ranging from 0 (never) to 5 . Teachers’ personal experiences have not been assessed via their general teaching experience. This approach has been chosen as it can be assumed that most contact teachers have had with individuals with ADHD within school was related to children with ADHD. Since the present study focuses on adults with ADHD, the general teaching experience would therefore not lead to a realistic estimation of teachers’ experiences with adults with ADHD. Moreover, even though it is widely assumed that the actual number of ADHD students taught in the past is directly related to years of teaching experience, it has been emphasized that this relationship is not significant (Kos et al. Reliability and Social Functioning, Ability to Take Responsibility and on the total stigma scale. The more teachers knew about ADHD the less they stigmatized on particular dimensions as indicated by small to medium effects. The present results on teachers’ knowledge about ADHD and frequency of contact to adults with ADHD are in line with the literature on educational approaches to the reduction of stigmatization. This literature reported positive effects of special trainings and education certifications on stigmatization of individuals with ADHD, whereas increased personal experiences with persons with ADHD have been shown to be ineffective (Bell et al. Data analysis revealed that the frequency of contact to adults with ADHD was not significantly related to stigma scores of teachers, while small to medium significant relationships were found on four dimensions and the total score for comparison participants, indicating decreased stigmatization with an increased frequency of contact. The lack of significant associations in teachers might have resulted from a rather frequent contact of teachers with children with ADHD and their parents who might partly also have suffered from the condition. Furthermore, teachers might have engaged with the topic of ADHD from an educational perspective via professional books, education programs as well as discussions with colleagues (Bell et al. In conclusion, even though previous research showed that teachers frequently present with incomplete knowledge about ADHD Bekle , the preThe present study must be viewed in the context of some limitations. Knowledge about ADHD was assessed with a self-rated scale rather than an objective measure of knowledge. The validity of self-evaluations can of course be questioned. A response bias in teachers’ self-evaluations about ADHD is reported by Kos et al.  who demo


In childhood, attention deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate levels of inattentiveness/disorganization, hyperactivity/impulsiveness, or a combination thereof. Although the criteria for ADHD are well defined, the long-term consequences in adults and children need to be more comprehensively understood and quantified. We conducted a systematic review evaluating the long-term outcomes (defined as 2 years or more) of ADHD with the goal of identifying long-term outcomes and the impact that any treatment  has on ADHD long-term outcomes.Studies were identified using predefined search criteria and 12 databases. Studies included were peer-reviewed, primary studies of ADHD long-term outcomes published between January 1980 to December 2010. Inclusion was agreed on by two independent researchers on review of abstracts or full text. Published statistical comparison of outcome results were summarized as poorer than, similar to, or improved versus comparators, and quantified as percentage comparisons of these categories.Outcomes from 351 studies were grouped into 9 major categories: academic, antisocial behavior, driving, non-medicinal drug use/addictive behavior, obesity, occupation, services use, self-esteem, and social function outcomes. The following broad trends emerged: (1) without treatment, people with ADHD had poorer long-term outcomes in all categories compared with people without ADHD, and (2) treatment for ADHD improved long-term outcomes compared with untreated ADHD, although not usually to normal levels. Only English-language papers were searched and databases may have omitted relevant studies.This systematic review provides a synthesis of studies of ADHD long-term outcomes. Current treatments may reduce the negative impact that untreated ADHD has on life functioning, but does not usually 'normalize' the recipients. In childhood, attention deficit/hyperactivity disorder (ADHD) is a psychiatric condition characterized by age-inappropriate levels of inattention, hyperactivity-impulsiveness or a combination of these problems ,2. The sThe short-term effect of ADHD treatment on symptoms is well characterized. Beyond this, the longer-term consequences have been the focus of numerous individual studies but comprehensive synthesis of the available data has yet to be conducted, thus the present systematic review was performed, focusing on comprehensive summary of long-term outcomes of ADHD. Short-term studies have demonstrated decreases in core symptoms with pharmacotherapy, but there is less evidence for longer-term benefits. Poor adherence and persistence on therapy, comorbidities, poor follow-up and difficulty in accessing consistent medication management from the healthcare system may contribute to difficulty in measuring long-term effects of medication ,20. Non-The importance of long-term studies has been recognized for more than a decade . ADHD trThe National Institute of Health in the US funded the Multimodal Treatment Study of Children with ADHD (MTA); this is one of the largest independent trials examining the effects on ADHD symptoms and long-term outcomes of different ADHD treatments including: intensive behavioral intervention, medication, these two treatments combined, or routine community care . In the Based on the potential for long-term persistence of ADHD into adulthood and equivocal reports on treatment, we initiated this evidence-based systematic review to understand the long-term outcomes of ADHD with emphasis on a comprehensive synthesis of published data. Given the large differences in study design and measurements used, we decided that using a binary feature common to all the studies ('significantly different' and 'not significantly different') to define outcome results for LTOs would allow us to summarize all the included studies in a non-statistical fashion. Binary variables are used to simplify data in clinical trials for ADHD quite frequently , ADHD Rating Scale (ADHD-RS) responder analyses). 'Long term' was defined as 2 years or more and 'outcomes' were defined as life consequences, distinct from symptoms.Our analysis sought to answer the research question: what are the long-term outcomes in participants with ADHD compared to baseline or controls and do long-term outcomes of ADHD improve with treatment ?Diagnostic and Statistical Manual of Mental Disorders fourth edition, text revision (DSM-IV-TR) diagnosis criteria that symptoms be present before age 7 years. Examining outcomes at age 10 years or older, would conservatively allow at least 2 years to pass before outcomes were assessed, in line with our definition of 'long term' as 2 years or more. All studies were peer-reviewed, primary research articles in the English language with full text available. Studies for which all participants were less than 2 years old were excluded. Meta-analyses, case studies, and literature reviews were excluded.Studies included in this review examined outcomes of (1)participants with untreated ADHD, and (2) participants with treated ADHD. Studies that only examined symptoms (as opposed to life-consequence outcomes) were excluded. The dataset comprised studies published between January 1980 to December 2010, including longitudinal studies with prospective follow-up or retrospective measures of 2 years or more; cross-sectional studies comparing two ages differing by 2 years or more; and single cross-sectional studies of participants age 10 years or older. Age 10 was chosen as the age limit in single cross-sectional studies, based on the The search methods for identification of studies are summarized below. More specific details of the search methods are provided in Additional File The country of origin of each study was noted. For some analyses, studies were grouped by world region . Studies from Northern America included those from Canada and the USA. Northern America was identified as a comparator because of the high percentage of participants who are treated for ADHD in these two countries.To assess risk of bias, we considered search bias, researcher bias, bias of individual research groups and bias due to changes in diagnostic criteria over time.In the analysis of outcome results, outcomes were considered different between study groups if they were reported to be statistically significantly different in the study or were presented by the study authors as obviously different so as to not require statistical comparison  Outcomes that were not statistically significantly different were considered 'similar' to the comparator. We summarized number of outcomes as one measurement and number of studies as a separate measurement, because some studies reported more than one outcome. A list of all the studies included in the final analysis is detailed in a separate publication .Our search method has been described in a previous publication . To idenBased primarily on title and abstract, these studies were reviewed manually and inclusion was agreed on by two researchers. This yielded 351 studies for inclusion in the analysis. A list of all studies included in the analysis has been published [All disagreements between researchers on study inclusion were resolved by examining the full text of the study. Studies included participants who were diagnosed with ADHD or symptomatic presentation of ADHD as reported by the authors of each study. Only those studies in which ADHD was the primary disorder under study were included. Studies included both naturalistic examination of ADHD course (vs non-ADHD controls or start-of-study baseline) and/or treated ADHD . Treatments included pharmacological, non-pharmacological, and/or multimodal treatment.Data from each study was manually extracted from the full text of the study to a database, including: (1) study location, (2) study sample size, (3) study length, (4) participant age range, (5) study support, (6) diagnostic criteria, (7) study type , (8) outcome measures, (9) outcome results, (10) comparator type, (11) treatment type, and (12) treatment duration. Outcome results were measured by dichotomizing all results into a binary variable of either 'poorer' or 'similar' outcomes, and with respect to outcomes with treatment, either 'benefit' or 'no benefit' with treatment. Many studies (44%) reported more than one outcome result, thus the number of outcome results is more than the number of studies. While the outcomes may be the item of interest, the number of studies from which these outcomes are derived is also informative and so is also reported.Outcome measures were compiled into nine major groups based on commonality of outcome characteristics Figure . This grThe number of outcome results in each outcome group can be seen in Figure Figure The ages of the participants were examined by studies of specific outcomes Figure . StudiesPoorer outcomes were generally observed in untreated participants with ADHD Figure . In all,Also found in the search were five studies that followed untreated participants with ADHD over 2 to 9 years and compared the long-term outcomes with the participants' status at baseline -46. Fourd of 0.33 (P = 0.04) for the difference in the number of traffic accidents in the last 6 months for participants with ADHD (0.29 ± 0.73 accidents) compared with non-ADHD controls (0.15 ± 0.43 accidents), albeit this small effect size represented almost twice the rate of accidents for the ADHD group [d of 1.03 (P < 0.001) for the difference in the parent-reported peer rejection scores for children with ADHD (0.45 ± 0.55) compared with non-ADHD controls (0.07 ± 0.23), while controlling for conduct disorder as a comorbidity [Many studies did not report effect size, and effect sizes varied among studies that did report it. For example, a study of driving outcomes reported a small effect size with a Cohen's HD group . Anotherorbidity . It is pTreated ADHD versus untreated ADHD was compared in 48 studies with 76 outcomes Figure . 'UntreaIn 42 studies, the outcome results (n = 76) of participants with treated ADHD were compared with the outcomes of non-ADHD controls. Again, more outcomes were observed than studies because some studies reported more than one outcome. Most such studies did not show normalization with treatment. Only 18 outcomes in 16 studies were similar for participants with treated ADHD versus non-ADHD controls. A total of 58 outcomes (76% of outcomes) in 35 studies, poorer outcomes were observed for participants with treated ADHD relative to non-ADHD controls.Benefit with treatment was analyzed according to specific outcome group for participants with treated versus untreated ADHD Figure . Note thpost-hoc hypothesis that less aggressive/consistent treatment of ADHD in the rest of the world compared with Northern America  versus the DSM-IV-TR [Four of the nine outcome groups exhibited a substantial percentage of no benefit with treatment. These four outcome groups were drug use/addictive behavior, antisocial behavior, services use, and occupation. A subanalysis of these four outcomes examined the SM-IV-TR ,50) may Further analysis of the results observed in Figure Overall, the results of the present study show that the long-term outcomes for participants with ADHD when left untreated were poor compared with non-ADHD controls, and that treatment of ADHD improved long-term outcomes, but usually not to the point of normalization. The outcomes that were studied (with ADHD symptoms deliberately excluded as an outcome) most often included drug use/addictive behavior, academic, and antisocial behavior. This was followed by social function, self-esteem, occupation, driving, services use, and obesity outcomes. These trends may reflect what is of most immediate interest to society in a given time period. For example, obesity, the least-studied outcome, has come into interest only recently, likely due to the increasing obesity epidemic in developed countries. Increasing interest in the epidemiology of obesity, led to the report of an association between obesity and ADHD in 2002 . Our datThe number of studies of long-term outcomes of ADHD has risen noticeably over the last 30 years, especially since 2000. This corresponds to a trend in awareness of the consequences of ADHD by clinicians, which appears to be on the rise .Treatment resulted in beneficial effects for many of the outcomes reported (72% of outcome results). These beneficial effects were observed as either significant improvement over pretreatment baseline, in comparison to untreated ADHD participants, or stabilization of the outcomes . DriThe four remaining outcomes that appeared to be least responsive to treatment were drug use/addictive behavior, antisocial behavior, services use, and occupation, with 67%, 50%, 50%, and 33% of reported outcome results demonstrating a benefit of treatment, respectively. Persistence in these cases may have to do with the existence of comorbidities, such as conduct disorder, which has for example, been associated with increased substance use disorders . OppositServices use may persist due to the incomplete amelioration of ADHD symptoms and impairments, possibly because although ADHD symptoms (like outcomes) respond to treatment, they are not completely normalized. Finally, continued impairment in occupation despite treatment may reflect the cumulative effects of ADHD symptoms and dysfunctioning over the lifespan. For example, low academic grades may later restrict employment or opportunities, impaired social function may precipitate extra friction with employers. The differential responsiveness of different outcomes to treatment is an intriguing area for future study.It should be mentioned that if we had categorized the study outcomes by age, such as 5 to 17 and over 18, we may have observed different areas of improvement depending on the age group. In combining the groups it is possible that this distinction is lost. One also needs to consider however, that certain categories such as occupation would not be as relevant to the 5 to 17 age group as opposed to academic achievement, which would apply to all groups.Even with treatment, worse outcomes were often reported for the ADHD group than for people without ADHD. This is not surprising, because although behavioral and drug treatment have been demonstrated to improve ADHD symptoms, these treatments do not necessarily normalize behavior to control levels ,57-61.For example, in one study of the effect of methylphenidate treatment on classroom measures, a 20 mg dose produced normalization in 30% to 60% of participants, (depending on the measurement used) although 53% to 94% showed improvement . Many stThe results of four studies included in this analysis that used both types of comparators within the same study ((1) non-ADHD controls and (2) untreated ADHD participants or ADHD participant's pretreatment baseline) were consistent with the present overall observations that there was clear improvement or stabilization with treatment of ADHD for social function, antisocial behavior, and academic outcomes, but not to the extent that non-ADHD control outcomes were matched ,39,48,62It should be noted that ADHD Rating Scale IV total scores decline (improve) between ages 5 to 7 and ages 14 to 18 in both Caucasians and African-Americans . Hyperactivity-impulsivity scores, especially, decline from ages 4 to 7 to age 14 and older in both boys and girls . TherefoFinally, we observed that treatment outcomes for the subgroup of domains that exhibit lower percentages of outcomes that benefit from treatment  were differentially improved when studies from Northern America were compared with those from the rest of the world . Based on this analysis there appears to be a geographical bias with regard to how responsive these four outcome group results are reported to be with treatment, a result that may be accounted for by regional differences in study design along with the resulting study population age, or diagnostic practices. In this very specific comparison, the numbers of studies from 'Rest of World' countries are low , thus as further investigation of these outcomes around the world are published, the results of this comparison may be clarified.Several possible risks of bias and limitations need to be considered regarding the included studies. First, a publication and cultural bias could have resulted from including only studies that were published in English. In addition, the analysis excluded unpublished studies that might have been presented at conferences, for example. Also, our search relied on search engines for 'peer reviewed' status. Moreover, by strictly adhering to Cochrane systematic review guidelines and only including studies that were identified in our original electronic search, it is possible that some relevant studies may have been missed, introducing a search engine and literature database bias. This bias was reduced by extensive searching of 12 databases. Nonetheless, we are aware of four studies that would have met inclusion criteria, but were not identified by the search engines due to a technical limitation or inadvertent search string exclusion. Examination of these studies shows that the reported results are consistent with the overall results of the present analysis. The results of these four studies are summarized briefly here. One study reported poorer outcomes for participants with ADHD versus non-ADHD controls with regard to academic achievement, occupational adjustment, antisocial behavior, relationships, and substance use . A seconResearcher bias could also be a possible source of bias in this analysis, however, this was reduced by having two researchers independently agree on the articles included and strict, simple inclusion criteria were established prior to searching.Other sources of bias could include biases of individual research groups, which was eliminated by including only electronically identified studies (as mentioned above) and not selectively including the studies of specific groups and omitting others. As observed, different study designs may also lead to different conclusions and taking comparators into consideration is critical. We included studies of various designs, which may minimize such bias.A further possible bias could arise from changes over time in diagnostic criteria or discrepancy between classification systems, specifically differences in the definition of hyperkinetic disorder (ICD-9 or ICD-10) versus ADHD (DSM-III/DSM-III-R/DSM-IV). Differences are less likely within classification systems . One stuThe present analysis supports the premise that without treatment, people with ADHD often experience poorer long-term outcomes and that treatment may improve the long-term outcomes of ADHD for some individuals, but not necessarily to the degree of healthy controls. Further analyses of the present data set will more comprehensively examine the impact of treatment on specific outcomes, as well as the impact of specific types of treatment modalities. The question remains as to whether the short-term benefits demonstrated by short-term drug or non-pharmacological treatment studies translate directly into long-term outcomes. Associations between specific short-term symptoms need to be examined as possible predictors for long-term outcomes, particularly because long-term studies are not always feasible. Future research should focus on the association between short-term symptom relief and long-term consequences and include longer-term follow-up of the consequences of childhood ADHD into the adult years.MS was an employee of Shire Pharmaceuticals, Ltd. when this analysis was conducted and when this manuscript was drafted. PH is an employee of Shire Development LLC, owns Shire stock and has stock options. HC has received consulting fees from Shire (nothing for contributing to this article). SY has received research funding or consulting fees from Janssen-Cilag, Eli-Lilly, Novatis, Flynn-Pharma and Shire (nothing for contributing to this article). She was a member of the UK NICE Guideline Development Group for ADHD. JK is owner of BPS International. BPS International received funding from Shire Development LLC to perform this analysis and participate in writing this manuscript. AGW is a consultant for BPS International and has been a consultant for Shire Development LLC. LEA has received research funding or consulting fees from Astrazeneca, Biomarin, Curemark, Lilly, Novartis, Noven, Seaside Therapeutics, and Shire (nothing for contributing to this article). Funded by Shire Development LLC, Wayne PA. An earlier version of this analysis was presented as a poster .All authors participated in designing and interpreting this analysis. JK, MS, and AW oversaw the literature search and analysis. All authors participated in writing portions of this manuscript and in reviewing and approving all manuscript drafts.MS was previously International Medical Director Clinical Development at Shire Pharmaceuticals and is currently Development Therapy Area Director at Norgine Pharmaceuticals. PH is Senior Director Global Health Economics & Outcomes Research at Shire Development LLC. HC is a Child and Adolescent Psychiatrist at Hôpitaux Pédiatriques de Nice CHU Lenval. SY is a Senior Lecturer in Forensic Clinical Psychology at King's College London, Institute of Psychiatry. JK is Founder and Chief Editor at BPS, International in San Diego, California. AGW is a consultant for BPS International, was formerly a consultant for Shire Development LLC, and is currently a Research Assistant Professor of Chemistry and Biomolecular Science, at Clarkson University in Potsdam, New York. LEA is a Child Psychiatrist, Educator, Professor Emeritus of Psychiatry, and a Principal Investigator in the Psychopharmacology and Related Research Program at the Ohio State University Nisonger Center.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/10/99/prepubSearch strategy details. These are the specific details of the search strategy used in this systematic review.Click here for fileTreatment types reported in the included studies. This list includes all the treatments mentioned in any study. Often a treatment may have been listed in the Methods of a study but no details were provided about dose or duration or age of treatment or frequency of treatment or separate connection to a specific outcome result, for example. It was possible to group treatment types by large category  and pool the reported outcomes in these categories.Click here for file