Migraine and Attention Deficit and Hyperactivity Disorder (ADHD) have been found to be associated in child and adolescent cohorts; however, the association has not been assessed in adults or otherwise healthy population. Assessing the comorbidity between ADHD and migraine may clarify the etiopathology of both diseases. Thus, the objective is to assess whether migraine  and ADHD are comorbid disorders.N = 26,456, age 18–65, 46% female) were assessed for migraine and ADHD using the ASRS ver 1.1 clinically validated questionnaire and self-reported migraine in a cross-sectional study. Logistic regression was used to examine the comorbidity between migraine and ADHD, and their associated endophenotypes.Participants from the Danish Blood Donor Study , . There was a significant interaction between age and gender, with comorbidity increasing with age and female sex. Post-hoc analysis showed that migraine with visual disturbance was generally associated with a marginally higher risk of ADHD and this was independent of ADHD endophenotypes.Migraine and ADHD were demonstrated to be comorbid disorders; the association with ADHD was most prominent for participants with migraine with visual disturbances. Future studies will elucidate which genetic and environmental factors contribute to migraine-ADHD comorbidity. Migraine is a complex and multifactorial headache disorder with a lifetime prevalence of 16–18% . MigrainAttention deficit and hyperactivity disorder (ADHD) is characterized by inappropriate levels of inattention, e.g., difficulty keeping attention, keeping track of details, and difficulty structuring trivial duties or following instructions, hyperactivity, e.g., speaks a lot, difficulty relaxing or sitting still, and impulsivity, e.g., often interrupts other people during conversations or answers a question before the question is finished . In contn = 572/675) found an increased prevalence of migraine when compared to community controls [n > 4mill) [n = 5671) [It is well established that migraine is comorbid with psychiatric traits, in particular depressive and bipolar disorder , 13, andcontrols , and sub> 4mill) . In line = 5671) . Accordi = 5671) , 20.Using a cross-sectional study of adults (age 18–65 years), we test the hypothesis that migraine is comorbid with ADHD in 26,456 participants using clinically validated questionnaires.www.DBDS.dk). In brief, the DBDS was initiated in 2010 and is an ongoing prospective research cohort and biobank that recruits participants between 17 and 67 years of age from blood banks across Denmark [From November 2015 to September 2017 voluntary blood donors were recruited as part of the Danish Blood Donor Study (DBDS)  or the ASRS items (n = 1108) of which n = 132 were missing both. The excluded individuals did not differ significantly with respect to age  compared to the study population. The excluded individuals were slightly older  when compared to the study population  . Importantly, the frequency of migraine in individuals excluded because of missing information in the ASRS questionnaire was similar to that of the study population (24.1%). Further, the frequency of ADHD in individuals excluded because of missing items in the SQM questionnaire was similar to that of the study population 4.2%.In total, 29,489 participants were given a questionnaire. We excluded 3033 individuals due to missing answers on either the SQM . The participants were asked two questions  of the original SQM. Participants who had a positive response to either of the two questions were considered to have migraine and are referred as migraine cases in this study. Individuals with missing information or who answered “I don’t know” were excluded. A detailed description of the SQM questionnaire can be found elsewhere . In shorDiagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) diagnostic criteria for ADHD and is the recommended version for clinical use in Denmark. Each of the 18 questions was scored on a five-point Likert scale ranging from never = 0 to very often = 4. In this study we use the optimal Kessler et al. 18-item ASRS scale score obtained by summarizing all items  as the primary outcome. The ASRS has been validated in multiple countries using different populations [Current self-reported ADHD symptoms were assessed using the current national recommendation for clinical assessment of adults by using the ADHD Self-Report Scale v1.1 (ASRS) , 25 tranulations –30. The ulations . A more ulations .The study population was described by numbers and percentages for categorical variables and as median and interquartile range (IQR) for continuous variables. Differences in distributions between participants with and without migraine and ADHD symptoms were analyzed using Fisher’s exact test or Mann-Whitney/Wilcoxon test .P-value< 0.05 was considered statistically significant. Post-hoc analyses were performed using different thresholds of the ASRS score (from 0 and 52), and single ASRS items (data not shown). To check if the specified model is appropriate for the data, the predicted and observed residuals were inspected for each analysis and no issues were observed.Logistic regression was used to analyze the association between migraine and ADHD (dichotomous variables) in the study population, adjusting for age, sex, and the interaction between sex and age, with migraine as the dependent variable. We used a logistic regression model with a binary outcome of either migraine, migraine with visual disturbance, or migraine without visual disturbances. We did not include sampling weights, as these are not available for DBDS. We calculatedthe regression in two ways including age as a quantitative trait or as a categorical trait . We report the derived odds ratios (OR) and 95% confidence intervals (CIs). A All statistical analyses were performed using the statistical package for R version 3.3.3: stat, basic, ggplot2, eeptools, cowplot, and GirdExtra.P < 1e-15 and P < 1e-15, respectively)  from the DBDS, of whom 24.2% screened positive for migraine , 2.61% screened positive for ADHD , and 0.90% reported having both migraine and ADHD , see Table P = 1.4e-14) including corrections for age, sex and the interaction of age and sex as covariates (Table P = 3.3e-11). Using the national prescription register we did not find any difference in frequency of triptan purchases with and without ADHD symptoms .There was an association between migraine and ADHD symptoms with OR = 1.81 , with migraine with visual disturbances showing a marginally larger effect than migraine without visual disturbances, notably with overlapping confidence intervals Fig. .Fig. 3AnWe address the comorbidity of migraine and ADHD symptoms in a healthy population of 29,489 adults using two clinically validated questionnaires (SQM and ASRS). Our results show a strong and statistically significant comorbidity between the two disorders which was irrespective of the threshold  with ADHD [The current study significantly supplements the sparse literature regarding the comorbidity between migraine and ADHD in adults by using a large, healthy study population of individuals who have not been exposed to chronic treatment for migraine or for ADHD. It supports the meta-analysis by Salem et al., showing OR of 1.3, consisting primarily of child and adolescence studies. This meta-analysis cohort consisted of a clinical case-control cohort,  was higher than reported by Fasmer et al. (28.3%) in a sample of ADHD patients with similar age and sex distribution . HoweverWe found that the comorbidity between migraine and ADHD was most prevalent among participants peaking at 52 to 53 years of age, and in the 40 decade compared to the 17–29 age group, which is somewhat inversely correlated with the age distribution of ADHD symptoms in the study population  were more often affected by co-occurring ADHD symptoms when compared to participants reporting no visual disturbances and combined Table , Fig. 2.The strength of the study is the large sample size and that chronic treatment of migraine and ADHD do not influence the results, e.g., treatment-induced migraine attacks. Furthermore, we used validated questionnaires to assess migraine and ADHD symptoms. In accordance with Danish clinical guides we use the recommended version of ASRS to assess ADHD. While a new version based on DSM V exists, a recent study found almost identical specificity and sensitivity of the two versions . FurtherWe demonstrate a significant corbobidity between migraine and ADHD in adults, and this is most prominent for participants with migraine with visual disturbances. These results contribute to the understanding of genetic correlation seen between ADHD and migraine and seeds future studies that will elucidate which genetic and environmental factors contribute to migraine-ADHD comorbidity.This study examined the association between migraine and ADHD in a large adult populationThere is a strong association between migraine and ADHD The association between migraine and ADHD seems strongest for individuals with visual disturbances


Emotion regulation deficits (ERD) are evident in about 34–70% of the adults with ADHD. In contrast to this, they are not considered in the diagnostic criteria of the disorder. In a recent study of our research group using confirmatory factor analysis, we modeled positive and negative emotion as well as emotion regulation skills along with the classical ADHD-core symptoms. We showed that negative affect and the failure to apply adaptive emotion regulation skills were distinct and indicative dimensions in adult ADHD. In this study, we used a person-centered approach based on cluster analysis to subtype patients on the presence or relative absence of ERD. This results in important information to individualize treatment decisions. We found two clusters, with cluster 2 showing high ERD that were associated with higher impairments indicated by depressive mood, negative affect and elevated psychological distress. There were also higher rates of comorbidity in cluster 2 such as somatoform disorders which were associated with ERD. Women were overrepresented in this cluster 2. Neuropsychological variables did not contribute significantly to cluster formation. In conclusion, ADHD in adults is a heterogeneous disorder with specific subgroups that need differential treatment approaches. Emotion generation can be described in four steps: (1) an emotional relevant situation occurs; (2) we direct our attention to this situation; (3) we judge and evaluate the situation which results (4) in an emotional reaction, that can then either be regulated or not2. A common model for emotion regulation (ER) is the one by Gross3. According to this model, emotions that need regulating have to be identified; an ER strategy has to be picked; and this strategy has to be implemented and evaluated whether the strategy is sufficient or needs adaptation. ER are thus all processes that enable us to influence our emotions in such a way as to when and how we experience and express them.Emotions are temporally limited, qualitative states that are associated with a change on the level of feelings, expression and physical states5. Recent studies in the field have shown that 40% to 70% of mental disorders are characterized by emotion dysregulation – with Attention Deficit/Hyperactivity Disorder (ADHD) being one of them7. This line of research points to ER and dysregulation as a biologically founded, dimensional, key transdiagnostic factor cutting across the specified R-DoC domains of the negative  and positive valence systems , the cognitive system , and system of social processes  as well as the arousal/regulatory system 8. As such, ER deficits distinguish between groups of healthy and mentally ill people, and are basically observable for all mental disorders with experimental research9, demonstrating that such deficits are central to the development and maintenance of psychopathology11.ER is proposed as an additional sixth factor within the Research Domain Criteria Initiative (RDoc) of the National Institute of Mental Health (NIMH) that reflects interactions among the other five domains14. A comprehensive review on ADHD and ER concluded that emotion regulation deficits (ERD) are evident in about 34–70% of adults with ADHD15. Those features are associated with mental health problems and unfavorable psychosocial outcomes in the mid- and long-term18. For instance, high levels of emotional lability explain a substantial portion of variance related to the morbidity and burden of adult ADHD12, and ERD was associated with significant functional impairments such as professional and familial instability19, as well as high-risk behaviors, such as risky sexual or driving behaviors20. Accordingly, ERD has been recognized as an important dimension of ADHD22, but is neither considered in the diagnostic criteria for the disorder in the Diagnostic and Statistical Manual of Mental Disorders24 nor in the International Classification of Diseases 10th revision25. Reasons why ERD had not been included as a third dimension aside attention deficits and hyperactivity/impulsivity are that those symptoms are not specific to ADHD27, vary substantially even in healthy controls28, and finally an explanation for the etiology of those affective symptoms in ADHD as well as a clear-cut definition of the various emotional symptoms29 is missing. The latter is also recognized in the current practitioner review on emotional dysregulation in ADHD29. Though there is no single, standard definition of ERD, it is generally regarded as a multidimensional construct entailing a lack of inhibition together with strong negative and positive emotions, and the failure to engage in self-regulatory actions27. In the review by Shaw and colleagues15 three different models for the association between adult ADHD and emotion regulation that are also presented in the recent practitioner review26 are discussed.In children, adolescents and adults with ADHD common co-occurring features relate to altered emotional experience like irritability, emotional hyper-responsiveness, rapidly changing moods and impaired emotion regulation as seen in reactive aggression, temper outbursts and poorly controlled behavior in emotionally colored situations32 based on a joint neurocognitive deficit, in the way that emotion regulation deficits in ADHD are underpinned by broader aspects of self-regulation and executive control33. For the second model it is argued that ERD entails some specific and dissociable neurocognitive components beyond executive dysfunctions34, that is ERD and ADHD are seen as correlated but distinct dimensions with overlapping, though separable neurocognitive deficits. This is supported by recent observations that emotion regulation independently contributed to the distinction between children with ADHD and typically developing children36. The third model regarding the observed overlap between ADHD and emotional dysregulation emphasizes the need to consider the combination of ADHD and ERD as a separate entity37. This view is supported by the observation that emotional dysregulation is more often seen in the combined ADHD presentation with a higher symptom load and a poorer outcome39 and by studies demonstrating that ADHD and bipolar disorder often occur together and aggregate in families at higher-than-expected rates40. Surman et al.37 for example showed that deficient emotional self-regulation was only elevated in siblings of adult patients with ADHD and deficient emotional self-regulation. At least it seems that ERD should be viewed as a defining feature of more severe adult ADHD14.The first model conceptualizes ERD as a core symptom of ADHD41. We modeled positive and negative emotion as well as emotion regulation skills along with the classical ADHD-core symptoms. We showed that negative affect and the failure to apply adaptive emotion regulation skills were distinct and indicative dimensions in adult ADHD41. Although this result supports ERD to be of special importance to ADHD, it neglects the obvious clinical heterogeneity of emotional symptoms observed in adult ADHD samples. Following the work by Nigg and colleagues42 on subtyping executive deficits in ADHD, the present study now uses a person-centered approach to model ADHD heterogeneity within the emotional dimensions we already established.In order to further illuminate the link between ERD and ADHD specified by those three conceptual positions, we recently used a confirmatory factor analysis approach2 for the variables entered into the k means cluster analysis performed in ALMO 15.The k means cluster analysis algorithm within ALMO 15 has the possibility to examine the classification variables regarding their influence for cluster formation. Table 2 of 0.185 was proposed, meaning that 18.5% of the variance can be explained by this partitioning. This solution possesses good quality criteria44. It can be seen in Table 2 values under the cut-off value for a medium effect45 of 0.06 and therefore contribute less to cluster formation. We therefore decided to exclude them from further analyses to obtain a stable cluster solution. Excluded were thus all neuropsychological variables ASTM, Qb+ Activity, Qb+ Impulsivity, Qb+ Inattention. Furthermore, we excluded CAARS-O inattention, and the SCID-II total number of symptoms regarding obsessive-compulsive, histrionic, and antisocial personality disorder.A two-cluster solution with an F value of 87.21 and an η46. Within the R package NbClust, which contains 30 indices for choosing the best number of clusters, we further elaborated the optimal number of clusters in k means. The results are displayed in Fig. We substantiated our analysis in R. Several indicators like average proportion of non-overlap (APN), average distance between means (ADM), figure of merit (FOM), Dunn index and Silhouette coefficient confirmed that the k means algorithm with two clusters should be the most appropriate grouping for our data It can be seen in Fig. The descriptive statistics of the classification variables in Table In order, to get a better understanding of the ERSQ differences between the two clusters, we compared our data to previously published clinical and healthy samples Table . Both, cThe variables not used for classification in Table 2 = 6.78, df = 1, p = 0.009). The effect size Cramér V signals a small effect with 0.1347.In cluster 1 the proportion of males is 67.4% (n = 122) while it is 54.4% (n = 111) in cluster 2. There is an association between cluster membership and gender . The effect size Cramér V signals a small effect with 0.29. Cluster 2 is dominated by patients with the combined type (85.0%) while in cluster 1 there is also a substantial proportion of patients with the predominantly inattentive type (35.6%).Table The two clusters differed significantly regarding the number of comorbid diagnoses . In cluster 2 there is a higher proportion of patients with 2 comorbid diagnoses demonstrating that patients in cluster 2 have a higher symptom load  than cluster 1 (10.5%). The effect size Cramér V signals a small effect. Cluster 1 and 2 do not differ significantly regarding affective disorders after Bonferroni correction and the resulting Cramér V shows a weak association.50 both of them were less skilled in ER, but compared to cluster 1, patients from cluster 2 reported more severe lack of skills: adult patients with ADHD from cluster 2 had highest ratings of emotional lability and reported the lowest ER skills, thus representing a subgroup of ADHD with severe ERD. Even compared to other clinical groups48 cluster 2 reported more impaired ER skills than comparison samples of patients with major depressive and adjustment disorders. In contrast, the total ER skill competence in cluster 1 was significantly higher than in samples of depressive, recurrently depressive and adjustment disordered patients.Empirically derived symptom profiles based on cluster analysis from adult patients with ADHD revealed two clusters. Compared to healthy samples51 and there was a predominance of the combined presentation of ADHD according to DSM with about 85%. In cluster 1 we found more heterogeneous presentations of ADHD with substantial proportions of the inattentive and the combined subtype. Replicating results of international studies52 patients with severe ERD in cluster 2 were found to have higher levels of emotional symptoms as indicated by their reduced positive affect, elevated BDI score and negative affect ratings. In line with previous findings, we found the severe ERD in cluster 2 to be associated with higher impairments in most clinical areas as indicated by elevated SCL-90 GSI scores and heightened prevalence of somatoform disorders, substance abuse disorders and affective disorders22. Furthermore, the severe ERD cluster showed more comorbidities. Those results are in support of Shaw’s model15 three (ADHD + ERD as a distinct entity) in which the subgroup of ADHD + ERD is associated with higher symptom load, poorer long-term outcome and comorbidity. As the self-ratings also indicate higher comorbidity of cluster 2 with personality accentuations  compared to normal, impulsive ADHD (as in cluster 1) attracts further emotional symptoms and adverse outcomes like a magnet.et al. did not find neuropsychological tests that differentiated adults with ADHD and deficient emotional self-regulation from adults with ADHD without deficient self-regulation52. This corresponds to our findings showing that neuropsychological variables did not contribute significantly to cluster formation.Surman 51. Recent data suggests that a substantial proportion of patients presenting with non-psychotic long-term mental health issues  fulfill a diagnosis of ADHD53.Most ADHD studies do not routinely assess emotional dysregulation. Therefore, it might be possible that these symptoms were misinterpreted as anxiety and/or depressive symptoms, especially in women with ADHD who have a higher rate of emotional dysregulation29. As outlined in the introduction, emotion regulation processes include more than global self-reports of valence of emotional experience and intensity of emotions3. Thus, our analysis is just an attempt to organize ADHD subgroups based on self-reports regarding neurocognitive and emotional dimensions, but it is only one, static piece of the puzzle. Future research needs to address the dynamics, as understanding “emotion regulation in action” seems to be a prerequisite to tailor personalized treatment options: different problems in real-life emotion regulation (e.g. insensitivity to own emotions vs. insensitivity to context) will suggest different therapeutic goals and imply distinct interventions. Dialectical behavior therapy (DBT), an intervention that specifically targets emotional dysregulation, with modifications according to the special needs of patients with ADHD, has shown moderate to large effect sizes in treatments of adult ADHD, and might in light of our findings be worthy to be considered for further research56.Our cross-sectional data only represent the static view on ER and ERD and miss the dynamics central to emotion regulationhttps://www.uni-marburg.de/de/fb04/team-christiansen/downloads/adulteadhs.pdf) based at the department of psychology at Philipps University Marburg, Germany. This clinic is specialized on diagnostics of adult ADHD and has a large catchment area. Our sample consisted of 385 individuals newly diagnosed with adult ADHD who were all medication-naive. They were examined by experienced licensed clinical psychologists on the basis of a detailed clinical history, the structured diagnostic interview for ADHD in adults (DIVA 2.0), a DSM-IV based clinical interview assessing the ADHD core symptoms in childhood and adulthood as well as psychological domains often impaired in adult ADHD57. Further, the Conners Adult ADHD Rating Scales (CAARS-L self- and observer-ratings), and the Qb+© 58 were used for diagnostic assessments. Additionally, the Amsterdam Short Term Memory Test (ASTM) was applied as a symptom validity measure59. The diagnosis was based on the DIVA 2.0 results in order to fulfill DSM-IV diagnostic criteria.All participants were recruited from our specialized adult ADHD outpatient clinic  aged a mean of 32.4 years (SD = 9.8) and 152 females (39.5%) aged a mean of 32.5 years (SD = 10.2). Twelve subjects (3.1%) had no school degree, 63 (16.4%) had basic schooling, 85 (22.1%) had finished secondary school, 199 (51.7%) had a grammar school (gymnasium) degree, and we had no information available from 26 patients (6.8%). Comorbidity was high in our sample, with 59 patients (15.3%) having a comorbidity in ICD-10 chapter V block F1 (psychoactive substance use), 5 patients (1.3%) in block F2 , 134 patients (34.8%) in block F3 (affective disorders), 68 patients (17.7%) in block F4 (somatoform disorders), 12 patients (3.1%) in block F5 , 7 patients (1.8%) in block F6 , 1 patient (0.3%) in block F7  and 2 patients (0.5%) in block F8 . Summing up the number of comorbidities, 199 patients (51.7%) had no comorbidity, 103 patients (26.8%) one comorbidity, 66 patients two (17.1%), 15 patients three (3.9%), and 2 patients (0.5%) four comorbidities.not at all/never to 3 = very much/very frequently). The long version consists of 66 items that result in the four factors inattention/memory problems, hyperactivity/restlessness, impulsivity/emotional lability, and problems with self-concept. Confirmatory factor analyses of the German version in healthy adults and ADHD patients supported this factor analytic solution61. The four subscales are significantly influenced by age, gender, and the number of years of education. Symptom severity decreases with age, males score higher than females on hyperactivity and sensation-seeking behavior, and females score higher than males on problems with self-concept. Overall symptom ratings are higher for individuals with less education. Test-retest reliability ranges between 0.85 and 0.92, sensitivity and specificity are high for all four subscales. The CAARS-L: S represents a reliable and cross-culturally valid measure of current ADHD symptoms in adults62. The same holds true for the CAARS-L: O, the observer version, which comprises ratings on the same items by a person who has a close relationship to the subject under examination63. The hypothesized factor structure was supported and the observer version also possesses satisfactory psychometric properties.The German version of the CAARS-L: S assesses ADHD symptoms in adults aged 18 years or older. Symptoms are rated on a Likert-type scale 65. It encompasses the ten items for positive and the ten items for negative affect, from the PANAS, adding additional items to cover emotions of stress, fear, anger, sadness, depression, and shame with 3 items each; guilt and disgust are measured with 1 item each. Furthermore, eleven items address the extent of coping emotions . In our study, we only used the two extended subscales for positive and negative affect with 25 items each.The EMO-Check Battery consists of two parts50 that assesses self-reports of adaptive responses to challenging feelings; it is based on the adaptive coping with emotions model66. The ERSQ is a 27-item self-report instrument employing a five-point Likert-type scale  to assess these adaptive emotional regulation skills in the previous week. There are nine subscales containing three items each: Awareness , Sensations , Clarity . Understanding , Acceptance , Tolerance , Readiness to confront distressing situations if needed to attain personally-relevant goals , Self-Support , and Modification . The total sum score was used for cluster analysis in the present study. When comparing our data to previously published data, we used the average score for ERSQ. As the ERSQ assesses ER skills as positive capacities, higher values indicate better skills, lower scores indicate deficient regulatory capacities. Internal consistencies are around 0.90, retest reliabilities range between 0.48 and 0.74. The total score correlated with the PANAS positive emotion subscale 0.41 and with the negative emotion subscale −0.3350. These data were confirmed in other studies67.The second part is the Emotion Regulation Skills Questionnaire (ERSQ)69 which is a 21-item self-report measure assessing somatic, behavioral, emotional, and cognitive symptoms of depression on a 4-point scale ranging from 0 to 3. The total score ranges from 0–63, with scores higher than 14 points indicate clinically relevant levels of depressive symptoms. The German Version proved satisfactory internal consistency (α ≥ 0.84) and construct validity71.Depressive symptom severity was assessed with the revised Beck Depression Inventory72. As the factorial validity for the subscales is debated, the present study only used the Global Global Severity Index which has proven as a valid indicator of psychological distress73.The SCL‐90‐R consists of 90 items  which assess nine primary symptom dimensions . In addition, three global summary scores can be calculated. Reliability of the scales is satisfactory (α = 0.79 to α = 0.89) for subscales in clinical samples; to excellent (α = 0.97) for the global psychological distress score; and validity has been confirmed74. Second, all personality disorders for which respondents endorsed sufficient criteria for a specific diagnosis are carfully evaluated by an interviewer in order to assign a formal diagnosis75. A modified version of the SCID Screen questionnaire resulted in a correlation of 0.84 between the number of criteria fulfilled in the SCID II interview and in the questionnaire. After adjusting the cut‐off level for diagnosis, the frequency of personality disorders found by the SCID screen questionnaire or the interview was almost the same with 58% and 54%, respectively; the overall kappa was 0.7876. We only used the questionnaire data in the present study which does not allow formal diagnoses. The self-defeating personality disorder is represented by 7 items, the dependent personality disorder by 8 items, the obsessive-compulsive personality disorder by 9 items, the negativistic personality disorder by 8 items, the depressive personality disorder by 8 items, the paranoid personality disorder by 9 items, the schizotypal personality disorder by 9 items, the schizoid personality disorder by 9 items, the histrionic personality disorder by 7 items, the narcissistic personality disorder by 16 items, the borderline personality disorder by 14 items, and the antisocial personality disorder by 15 items. We chose the variables contributing significantly to separating the data into clusters and compared the resulting groups regarding the number of “yes” answers in each personality disorder being aware that we were not able to diagnose the specific personality disorder on an individual basis.The SCID-II assesses personality disorders according to DSM-IV in a two-tiered procedure. First a 119-item self-report screening questionnaire, which uses a Yes/No response format, asks for each of the diagnostic criteria of all personality disorders listed within DSM-IV77. It is presented as a test of short-term memory and attention. Five semantically related words are shown for 8 seconds. They should be read aloud and remembered. Then, a simple arithmetic problem is given. Afterward, another five words are presented, and the subject is required to identify the three words that were previously shown. The score for the 30 tasks totals a maximum of 90 points. The reliability of the test is satisfactory. The internal consistency in different samples is around 0.90. In a sample of mixed neurological patients, test–retest correlation was 0.85 within an interval of 1 to 3 days77. A different study reports a reliability coefficient of ϕ = 0.92 based on the comparison of actual versus diagnosed group membership in an experimental simulation study78. The test also demonstrates good validity. The cutoff value for the ASTM is ≤84 points. Sensitivity for lack of motivation was 91%  and specificity was 89% . Healthy controls from age 9 on master this test almost perfectly. Patients with neurological disorders, such as concussions, brain tumors, multiple sclerosis, or difficult-to-treat epilepsy, rarely have difficulties in handling this test, provided they do not have serious cognitive deficits. The test has been shown to identify ADHD patients with severe attention impairments59.The ASTM measures negative response bias and insufficient motivation in psychological examinations79. The ratio of target to nontarget stimuli is 25:75. During performance of the CPT, the movements of the participant are recorded with an infrared camera tracking a reflective marker attached to a headband worn by the participant. The infrared camera is placed about 1 m away from the participant, who is sitting in front of a computer screen. Participants are seated on a chair with back support but no armrest, to assure that they sit comfortably during testing, but do not adopt a reclining posture. Participants’ activities during the test are recorded by reading the coordinates (X and Y) of the headband marker. The position of the marker is sampled 50 times per second, with a spatial resolution of 1/27 mm per camera unit. Normative data have been gathered from 1,307 individuals between 6 and 60 years of age for both versions of the test (QbTest 6–12 and Qb+) with an even age and gender distribution80. Q scores are derived for hyperactivity, inattention, and impulsivity. They are interpreted similar to Z scores with a mean of 0 and a standard deviation of 1. A Q score ≥1.5 is regarded as an atypical result.The Qb+ is a CPT measuring sustained attention with a 1-back working memory task  combined with a simultaneous high-resolution motion tracking system. It separately assesses hyperactivity, inattention, and impulsivity with nine parameters and takes 15 to 20 minutes. Presented stimuli are a blue circle, a blue square, a red circle, and a red square. A response key is to be pressed when two identical stimuli are shown in succession. The task requires stimulus information to be maintained in working memory until the next stimulus is presented and a matching process can be done43. The k-means procedure as a person-centered approach identifies relatively homogeneous subgroups while maximizing the variability between clusters. Calculations were made with ALMO 15 , which includes a k-means algorithm able to handle the different scaling of our variables and the large sample size43. This program proposes the optimal number of clusters and provides statistical measures to evaluate the appropriateness of several cluster solutions . Partial η2 represents the effect size in a general linear model (GLM). It is an omnibus effect size when examining the cluster solution as a whole and a partial η2 when examining the contribution of single variables to the cluster solution. η2 of 0.01 can be regarded as small, 0.06 as medium, and 0.14 as large81. Variables were first examined regarding their importance for cluster formation as -to the best of our knowledge- this is not available in any R package. We substantiated our analyses in R (https://cran.r-project.org/) as several R packages offer more detailed options. We applied R packages clValid82 and NbClust83 to determine the best clustering algorithm and the optimal number of clusters46. Variables not used for classification further characterized the two clusters on a descriptive level. If standard deviation was close to the mean, Huber’s M estimators were also listed. Differences between the two clusters on metric variables were evaluated by Welch tests which were shown to be robust against violations of normality and homogeneity of variance84 and by using effect size Cohen’s d with 0.2 showing a small, 0.5. a medium, and 0.8 a large effect47. In case of multiple testing, p values were adjusted by Bonferroni correction85. Priority should be given to the analysis of effect sizes as there is a critical debate over Null Hypothesis Significance Testing (NHST) and its resulting p values87.Cluster analysis is an iterative process. We therefore first performed k-means cluster analyses generalized to all scales of measurement with squared Euclidean distances2 -Tests and effect size Cramér V of which a value ≥0.40 signals a large effect79, and by Fisher’s Exact Tests.Categorical variables were analysed by χThe study was approved by the Ethics Committee of the Department of Psychology at Philipps University Marburg, Germany.


Staphylococcus aureus and Escherichia coli , using flow cytometry (FC) to reveal its antibacterial action mechanisms. Effects of MkH on membrane potential, membrane integrity and metabolic activity were assessed using different fluorochromes in a 180 min time course assay. Time-kill experiments were carried out under the same conditions. Additionally, MkH effect on efflux pumps was also studied in an E. coli strain with an over-expression of several efflux pumps. Exposure of bacteria to MkH resulted in physiological changes related to membrane potential and membrane integrity; these effects displayed slight differences among bacteria. MkH induced a remarkable metabolic disruption as primary physiological effect upon S. aureus and was able to block efflux pump activity in a dose-dependent fashion in the E. coli strain.Several studies have explored the antimicrobial properties of manuka honey (MkH). However, the data available regarding antibacterial action mechanisms are scarcer. The aim of this study was to scrutinize and characterize primary effects of manuka honey (MkH) upon the physiological status of  The emergence of multi-drug-resistant pathogens is one of the most pressing concerns of public health and food industry worldwide; the situation is especially disturbing in the case of bacteria ,2.The excessive and inadequate use of antibiotics clearly contributes to the development of resistance, usually through genetic changes . CommuniStaphylococcus aureus and Escherichia coli are commonly involved in infections of both community and healthcare settings and are amongst the leading causative agents of food-borne infections worldwide. In addition, according to the last surveillance of antimicrobial resistance in Europe, these bacterial species currently present resistance to multiple antimicrobial groups [Leptospermum species, native to New Zealand and Australia. The antimicrobial activity of this variety of honey is connected with common factors such as, osmotic pressure (as result of the high concentration of sugars), acidity or oxidative stress. Furthermore, MkH exhibits non-peroxide antibacterial activity related to the presence, in high concentrations, of compounds such as methylgloxal or leptosin [l groups . The abol groups ,8,9 whicleptosin ,11.Despite the numerous studies on the antibacterial properties of honey it use as an antibacterial agent remains underestimated, partly due to the lack of comprehensive scientific evidence supporting its use ,12,13. TFlow cytometry (FC) has been widely applied to study the antimicrobial susceptibility and characterization of resistance mechanisms of several microorganisms ,16,17,18Escherichia coli and Staphylococcus aureus in a time course assay, using a FC protocol which was adapted for the purpose. This research is essential to understand honey’s targets when acting as an antimicrobial and to further explore the therapeutic potential of this natural product.The aim of this study was to evaluate the physiological changes induced by MkH upon S. aureus CECT 86 (a) and E. coli CECT 515 (b)) following application of the two MkH concentrations under test in comparison to the non-treated cells.p < 0.05). CFU counts of the treated S. aureus decreased progressively throughout time up to 120 min of treatment, time in which CFU counts stabilized  (p < 0.05).A significant growth reduction was registered soon after 30 min of incubation with both concentrations (abilized a. On the < 0.05) b. SignifS. aureus CECT 86 (a) and E. coli CECT 515 (b), in comparison to non-treated cells.S. aureus treated with 10% (w/v) of MkH displayed a significant increase of fluorescence after 120 min of incubation (p < 0.05). Interestingly, after this time, cell membrane seemed to repolarize, re-establishing their membrane potential  (w/v) of MkH resulted in a time-dependent increase of depolarized cells from 60 min  up to 180 min  of treatment. Significant differences were observed between both treatments at 60 min (p < 0.01), 120 min (p < 0.05) and 180 min (p < 0.001).= 0.068) a. ConverE. coli, cells treated with 20% (w/v) of MkH displayed a significant increase of fluorescence after 120 min of incubation  (w/v) of MkH resulted in a time-dependent increase in the amount of depolarized cells between 60 min  and 120 min  of exposition (p < 0.001), 120 min (p < 0.001) and 180 min (p < 0.001).Regarding < 0.001) b. The apposition b. IntereE. coli cells exhibited higher membrane depolarization than S. aureus cells exposed to the same concentration of MkH (20% (w/v)). However, E. coli cells seemed to be able to restore MP progressively after 120 min of treatment, regardless of the honey concentration.These findings support the relevance of honey concentration and time of exposition upon the increase of cell membrane depolarization in both bacteria.S. aureus CECT 86 (a) and E. coli CECT 515 (b) compared with non-treated cells.S. aureus membrane were observed (p < 0.01) increasing up to 180 min . On the other hand, cells treated with 20% of MkH showed PI-intake after 60 min , increasing progressively following 120 and 180 min of treatment . Significant differences were also registered between both experimental conditions at 60 min (p < 0.05), 120 min (p < 0.001) and 180 min (p < 0.01).After MkH exposure, minor—yet significant—modifications in observed a, but noE. coli treated with 20% of MkH showed no significant differences when compared with viable non-treated cells. Conversely, the treatment of E. coli cells with 30% (w/v) of MkH resulted in a time-dependent increase of SI from the early stages of the treatment at 30 min  up to the end at 180 min . Significant differences were observed between the two treatments conditions at all time points.Differently, S. aureus CECT 86 cells, presented as MIF .w/v) of MkH MIF decreased to a value of 15.87 (p < 0.001) and decreased progressively up to the end of treatment . The drastic reduction observed on MIF values could be explained by an extremely reduced metabolic activity or by the loss of membrane integrity, which may lead to the loss of fluorescence. Cells treated with 10% (w/v) of MkH showed significant PI-intake after 120 min of treatment. However, metabolic activity decreased after 30 min of exposure at a similar concentration of honey. Thus, the second hypothesis may be discarded, at least during the first stages of the treatment.MIF displayed by viable non-treated cells increased slightly up for 180 min but without significant differences along the time. Soon after 30 min of treatment with 10% (w/v) of MkH  and 60 min of treatment at 20% (w/v) . This data suggests that metabolic inactivation is less dependent from MkH concentration and treatment time than membrane depolarization and membrane lesion.Although slight differences were registered between both treatment conditions, they were not statistically significant . In addiE. coli AG100TET are presented in w/v) , 30% (w/v) , 40% (w/v)  and 50% (w/v) . In addition, no significant differences were observed between MkH-treated cells at 50% (w/v) and positive control cells , suggesting that MkH promotes efflux pumps blockade in a dose-dependent fashion.The results obtained regarding efflux pumps blockade of The emergence of multi-drug-resistant bacteria poses a great worldwide problem for the agriculture and food industries and rises public health concerns ,2. This S. aureus and E. coli through FC. The ability of bacteria to deal with environmental stresses determines their success to survive. Following the exposure to MkH, several physiological changes were registered, both in S. aureus and E. coli. The effects of MkH on cell viability, cytoplasmic membrane potential and membrane integrity were evaluated on S. aureus CECT 86 and E. coli CECT 515. Effects of MkH on metabolic activity were assessed on S. aureus CECT 86. Finally, the effect of MkH on efflux pump activity was valued in E. coli AG100TET strain.The present study provides new insights regarding the physiological effects of MkH upon S. aureus and E. coli cells were not able to recover from the MkH induced alterations and lost their viability as result of physiological changes. This effect seems to be irreversible up to the maximum time tested, corroborating data published in other studies [A significant reduction of bacterial growth was observed after MkH exposure. This data suggest that  studies ,12.S. aureus and E. coli were not previously described.An essential aspect of bacterial adaptation to environmental conditions is the equilibrium of ion concentration inside and outside of bacteria, which determines cell membrane potential (MP) . In thisS. aureus after MkH treatment was found [Pseudomonas aeruginosa (another Gram-negative bacteria), there was evidence that large amounts of extracellular material result of cellular lysis [oprF gene expression in P. aeruginosa population treated with MkH was related to deficiencies on membrane integrity [E. coli, such deficiencies might be related to ompA gene, orthologue to oprF with significant amino acid similarity [On the other hand, the loss of membrane integrity represents a meaningful damage for bacteria. The results obtained in this study reveal that the treatment time and specially the MkH concentration are key factors regarding the induction of membrane injury in both bacteria. Moreover, these results evinced that the effect of MkH on membrane integrity seems to be slightly different between Gram-positive and Gram-negative bacteria. Previous studies have also detected such differences among both types of bacteria, while limited or no evidence of cell lysis of as found ,25. In car lysis ,27. In amilarity . NeverthS. aureus metabolism was studied using calcein-AM. This compound is a cell-permeant esterase substrate that measure enzymatic activity [S. aureus cells as an early event. Previous studies, comprising genomics and/or proteomics, demonstrated that MkH induces a reduction in the expression of genes and proteins involved in energy metabolism of S. aureus [E. coli cells was not assessed because Gram-negative bacteria are not permeable to calcein-AM [S. aureus encourage the search of other alternatives to evaluate metabolic disruption. Moreover, studies on E. coli [P. aeruginosa [E. coli using FC, could confirm metabolic status alterations, which might be related with the results observed in other studies.The influence of MkH on activity . Esteras. aureus ,10. Howe. aureus . The conlcein-AM . Neverth E. coli , as wellruginosa  confirmeE. coli AG100TET, a bacterial strain which over-expresses several efflux pumps when exposed to high concentrations of tetracycline. Efflux pumps can be specific to antibiotics, although most of them are multidrug transporters that are capable to pump a wide range of unrelated compounds and thus, significantly contribute to multidrug resistance [E. coli demonstrated that following exposure, some genes belonging to the EvgAS regulon—used by E. coli in adaptive responses to acid, osmotic and drug resistance—were upregulated [E. coli.The effect of MkH on efflux pump activity was also assessed on sistance ,32. Somesistance ,33,34,35egulated . This diThis study demonstrated that MkH induced effects on the physiology of bacteria, as result of their effort to adapt and overcome from a stressful environment. MkH effects did not occur as an initial event, with the exception of metabolic disruption, and were dependent on honey concentration. However, the final result observed was the reduction of cell viability. Due to its complex composition, with multiple active components, MkH acts in a multifactorial way upon several cellular target sites, as was confirmed in this study, which hinders the development of bacterial specific defence mechanisms and, therefore, resistance ,36.S. aureus. Other effects, such as the membrane potential imbalance and the membrane injury were also detected in both reference strains. The efflux pump blockade observed in E. coli AG100TET was dependent on honey concentration. This finding could encourage further studies to know the effect of MkH-antibiotic combinations over bacterial physiological effect, addressing especially those which are usually extruded from bacteria by efflux mechanisms.The global escalation in antibiotic resistance means that alternative antimicrobials are essential. Our results demonstrate that MkH induced a remarkable metabolic disruption as primary physiological effect on Data presented in this study are in accordance with previous findings on antibacterial action mechanisms of MkH, carried out using other methodologies. This fact corroborate that FC is a valuable tool for analysing physiological states of bacteria exposed to honey.Further studies using other varieties of honey with demonstrated antibacterial activity are necessary to elucidate whether the action mechanisms described for MkH are similar in other types of honey.Staphylococcus aureus (CECT 86) and Escherichia coli (CECT 515) from the Spanish Type Culture Collection were used as Gram-positive and Gram-negative bacteria models, respectively. Reference strains were used instead of clinical or resistant isolates in order to avoid a possible altered response mechanism to MkH exposure, which could confound the effects of honey upon bacteria. In addition, E. coli AG100TET (kindly provided by Dr. Miguel Viveiros), an AG100 progeny strain, which over-expresses several efflux pumps when exposed to high concentrations of tetracycline [acycline , was use600 absorbance of 0.100, approximately corresponding to 1 × 108 CFU/mL. This culture was prepared by transferring an isolated colony (from a fresh culture in Mueller Hinton (MH) agar) into MH broth; overnight culture was then incubated for 16 h in 50 mL of MH broth. The flask was placed in a shaker incubator at 37 °C and 180 rpm. Aliquots were taken every half hour to read the absorbance at 600 nm until growth curves reached stationary phase. At the described conditions, the exponential growth phase of S. aureus occurred between 2 h and 8.5 h, and between 1 h and 8 h for E. coli strains  broth were inoculated in an Erlenmeyer flask with an overnight culture of bacteria to obtain an optical density OD strains a.600 absorbance of 0.100. Once the exponential phase was reached after incubation at 37 °C and 180 rpm during 2.5 h for S. aureus and 1.5 h for E. coli strains, a bacteria cell suspension corresponding to 108 bacteria cells/mL was prepared for the flow cytometric assays  for S. aureus and 20 % (w/v) for E. coli strains [Manuka honey MGO 550+   was used in this study. Minimal inhibitory concentration (MIC) and minimal lethal concentration (MLC) were previously determined according to the Clinical and Laboratory Standards Institute M07-A9 protocol . MIC and strains .A stock solution of 0.8 g/mL of the MkH sample (the maximum concentration of honey able to solubilize) in MH sterile broth was prepared in sterile Falcon tubes to carry out the following assays. Complete dissolution of honey was achieved with intense agitation.S. aureus CECT 86 and E. coli CECT 515. The concentrations of MkH tested were selected according to the susceptibility results: 10% and 20% (w/v) for S. aureus and 20% and 30% (w/v) for E. coli [8 bacteria cells/mL in exponential growth phase) and variable volumes (between 0.125 and 0.375 mL) of the stock solution of MkH to achieve the target concentrations were mixed and incubated for 30, 60, 120 and 180 min at 37 °C and 180 rpm  for 5 min. The supernatant was discarded and the pellets were washed twice with 1 mL of phosphate saline buffer  in order to prevent antibacterial carryover. Afterwards, bacteria were resuspended with 1 mL of PBS. Cell viability was determined by counting colony forming units per mL (CFU/mL)  c. BrieflThe physiological status of bacterial cells following exposure to different concentrations of MkH in a time course assay were assessed by FC. Previous FC assays ,21,40,41w/v) for S. aureus CECT 86, 20% and 30% (w/v) for E. coli CECT 515) were incubated in sterile Eppendorf tubes at 37°C and 180 rpm for different times . In all assays, the final volume was 1 mL. For each strain, non-treated cells were used as negative control and cells treated with 1 mL of ethanol 70% (w/w) as positive control  equipped with 3 photomultipliers, standard filters, and a 15 mW, 488 nm argon laser, using Cell Quest Pro software version4.0.2 . Data was recorded for 20,000 cells for each assay.Due to honey characteristics and the sensitivity of some fluorochromes to acidity, the pH evaluation was performed for each assay.The effect of MkH on cell membrane potential of the reference strains was evaluated using bis- trimethineoxonol (DiBAC4 (3); Sigma-Aldrich, Munich, Germany) as described by Teixeira-Santos et al. 2015). After honey treatment, cells were incubated for 15 min in the dark at 37 °C and 180 rpm with 0.5 mg/L of DiBAC4 (3). DiBAC4 (3) enters only depolarized cells, where it binds reversibly to membrane and intracellular components, resulting in an increased fluorescent signal [15. AfterCell membrane integrity of the two reference strains was assessed with propidium iodide  staining. After honey treatment, bacteria were stained with 1 mg/L of PI for 30 min at 37 °C and 180 rpm in darkness. PI is a cell viability marker which enters cells only when membrane has been seriously injured and exhibits fluorescence after binding to nucleic acids . FI was S. aureus CECT86 were evaluated using the fluorogenic substrate calcein-AM  at a concentration of 1 mg/L for 120 min at 37 °C and 180 rpm in darkness. Only metabolically active cells are able to hydrolyse calcein-AM to a fluorescent compound by intracellular esterases. This compound accumulates inside cells with intact membranes and increases their fluorescence. When cells have an injured membrane, impermeant end products will be quickly lost to the extracellular space, resulting to a decreased fluorescent signal [Metabolic changes induced by MkH on E. coli AG100TET strain, following the protocol described by Paixão et al. (2009) involving accumulation and efflux assays using 1 mg/L of ethidium bromide . Bacteria treated with 20 mg/L of chlorpromazine , an efflux pump inhibitor, was used as positive control. EtBr is a common efflux pump substrate; under normal conditions EtBr enters the bacteria and is rejected to outside by efflux pump action. In case these pumps are blocked EtBr accumulates inside the bacteria, increasing its fluorescence [The effect of MkH on efflux pumps was evaluated in rescence .In this assay four concentrations of MkH  were tested. Bacterial suspensions were incubated for 60 min at 37 °C and 180 rpm in darkness. The fluorescence intensity (FI) was measured at FL3. MIF was used to evaluate treatment differences.All experimental procedures were replicated three times using fresh culture preparations; the results were expressed in all cases as mean values and respective standard deviationsp < 0.05 was considered to be significant.The statistical analysis was performed using IBM SPSS statistics v.24.0 . All variables were tested for the assumptions of normality and homoscedasticity. Paired-sample Student’s t-test or Wilcoxon signed rank test (parametric or nor parametric test depending on the characteristics of the variables) were used to evaluate if there were any differences between non-treated bacteria and MkH treated bacteria at the different time points sampled in each assay. In addition, unpaired-sample Student’s t-test or Mann-Whitney test (parametric or nor parametric test depending on the characteristics of the variables) were used to compare the differences between the two MkH concentrations tested in each assay.


In different ethnic groups, birth related factors have shown significant influence in the etiology of Attention deficit hyperactivity disorder (ADHD). Based on these interesting findings, we aimed to investigate association between different pre- and post natal variables and ADHD associated traits in Indian subjects.ADHD Probands recruited based on the DSM-IV, were assessed by the Conner’s Parent Rating Scale for behavioral problem (BPr), inattention (IA), hyperactivity (HA) and ADHD index (AI). Impulsivity (Imp) was assessed by the Tsukuyama scale.P < 0.05).Higher paternal (Std β = 0.23) and lower maternal (Std β = 0.21) age showed significant association with Imp of the probands. Higher paternal age also revealed association with BPr (Std β = 0.18). Age of onset was distinctly associated with AI (Std β < 0.16) while developmental delay was negatively correlated with BPr, Imp, IA and birth weight (r < − 0.13); also confirmed by Posthoc-ANOVA  contains supplementary material, which is available to authorized users. Attention Deficit Hyperactivity Disorder (ADHD) is a neuro-developmental disorder, mostly detected in school-going children/adolescents , 2. AparBeing a multigenic disorder, disease etiology is influenced by complex interplay between biological and environmental factors. As compared to age matched healthy children, ADHD probands often suffer from delayed maturation of the brain , 7. MateSeveral reports show that prevalence of ADHD is increasing in India –25. HoweN = 212), age 6–14 years (M:F 189:23) were recruited following the Diagnostic and Statistical Manual-IV- Text Revised (DSM-IV TR) [ADHD probands (M-IV TR)  and detaBPr, IA, and HA was assessed by DSM-IV-TR  and ConnChildren diagnosed primarily with ADHD were considered for the study. Those with only psychiatric problems including pervasive developmental disorders, any form of mental retardation (IQ ≤ 70) and fragile-X syndrome, were excluded.Order of the child was scored as 1 for the 1st child, 2 for the 2nd child and likewise. Probands with no developmental delay were grouped under 1 while those with only delayed speech was considered as 2 and with delay in motor as well as other milestones as 3. Probands delivered normally were scored as 1 while probands delivered by caesarean section and forcep’s were scored as 2 and 3 respectively. Preterm delivery was scored as 1, full term delivery was scored as 2 and post-term deliveries were considered as 3.All analysis was done using the SPSS version 32. Each and every necessary assumption was checked before running the appropriate program. Principal Component analysis (PCA) was performed for the entire dataset excepting for nominal predictors like Term and Order which had low number of individuals in the third group. Initial check for sphericity and adequate sampling were done for the total dataset.Mean age of the probands was (8.39 ± 3.34). Average paternal age (P_Age) was 34 years 34.14 ± 6.19) while maternal age (M_Age) was 27 years (27.04 ± 5.26). Most of the probands were delivered at full term, while 20% were premature and only few were hypermatured . However, sampling adequacy was low (KMO = 0.643) and hence, a preliminary analysis was performed using a varimax rotation model. The extracted communality values showed percentage of variance that could be explained by the corresponding model  and Int_Per-Imp (P = 0.02). Though the overall model was not significant for DSM-AI and Schl_Work_Imp (P > 0.10), it was considered further due to closely significant T scores . Higher P_Age and lower M_Age showed association with higher Int_Per_Imp (P = 0.02 & 0.04 respectively). AI was positively influenced by higher age of onset (P = 0.06). BPr, Int_Per_Imp and Schl_Work_Imp showed negative correlation with developmental milestones (P = 0.08–0.007). No other models showed any significant correlation.Based on the nine outcome variables, nine different models were analyzed  were noticed in the preterm as compared to full term children (Table P < 0.05).Lower scores for BPr (P = 0.02) and AI


Low birth weight (LBW) is an important indicator of newborn survival. It is associated with higher risk of morbidity, mortality and long-term health consequences. Little has been done on incidence and recurrence risk of LBW in developing countries including Tanzania. This study aimed to determine the incidence and recurrence risk of LBW among women who delivered at Kilimanjaro Christian Medical Center (KCMC), Tanzania.A hospital-based prospective cohort study was conducted using maternally-linked data from KCMC birth registry between 2000 and 2010. A total of 26,191 women delivered singleton live babies during the study period. Of these, 4,603 (17.6%) had subsequent pregnancies. The recurrence risk of LBW was estimated using a multivariable log-binomial regression model. A robust variance estimator was used to account for correlation between births of the same mother.The incidence of LBW was 7.1%. The absolute recurrence risk of LBW was 28.1%. This corresponds to a relative risk (RR) of 5.08-fold, 95% CI 4.01–6.45). Antenatal care visits (<4) , preterm birth , positive HIV status (RR: 7.49: 95% CI 3.91–14.36) and preeclampsia  in the first pregnancy were important predictors of LBW recurrence.The incidence of LBW and its recurrence was high in the study population. Women with previous history of LBW had higher risk of recurrent LBW in subsequent pregnancies. Identification of factors associated with LBW recurrence, proper post-partum care management to ensure Healthy Timing and Spacing of Pregnancy, Pre-conception care and close clinical follow-up during subsequent pregnancy may help reduce LBW recurrence. Low birth weight (LBW) is defined as the newborn weight at birth of less than 2500 grams regardless of gestational age –3. It isNumerous factors have been associated with increased risk of LBW. These include preeclampsia, eclampsia, placental abruption, placenta previa, premature rupture of membrane (PROM), maternal background characteristics such as poor nutrition, smoking during pregnancy, maternal illness during pregnancy, high parity, low maternal education, high maternal age, low maternal Body Mass Index (BMI), inadequate prenatal attendance, medical conditions such as HIV positive status of the mother and maternal anemia, environmental as well as genetic factors like history of mother having been born with LBW and history of LBW in prior pregnancies , 4–8.The risk of LBW has been reported to recur between pregnancies. Women with previous history of LBW have been reported as potential carriers of the recurrent risk and tend to have higher recurrence risk of LBW in their subsequent pregnancy compared to those who had a previous normal birth weight baby –14.A number of factors have been associated with increased risk of recurrent LBW including history of LBW, high parity, both extreme maternal age, smoking during pregnancy, low BMI, HIV positive status, lower socio-economic class, previous history of preterm birth, female sex of the newborn, low quality antenatal care and low maternal weight gain during pregnancy , 15, 16.Understanding the recurrence risk of LBW and associated factors may help to design a focused intervention for groups of mothers at high risk of LBW recurrence. This study aimed to determine the incidence and recurrence risk of LBW among women who delivered at Kilimanjaro Christian Medical Center (KCMC), Tanzania.A hospital-based prospective cohort study was conducted using maternally-linked data from KCMC birth registry for women who delivered live singletons between 2000 and 2010. KCMC is one of the four referral hospitals in Tanzania which is located in Moshi, Kilimanjaro region in North of Tanzania. The hospital receives women from nearby communities and referrals from the nearby regions such as Arusha, Manyara and Tanga. The hospital has an average of 4,000 deliveries per year. By the end of December 2010, a total of 26,191 women were recorded at birth registry to have been delivered at KCMC. These women contributed to 30,800 siblings.The study utilized KCMC maternally-linked data which are available at the computerized KCMC medical birth registry. The KCMC medical birth registry has been operating since July 2000. The detail of the medical birth registry has been well described elsewhere . All womTrained midwives collected all information from mothers using a standardized questionnaire within 24 hours of hospital delivery, or as soon as a mother has recovered from birth. Furthermore, additional information was extracted from patient files while mothers are also asked to bring their antenatal cards for more clarification on prenatal information such as antenatal care visits, maternal weight and blood pressure measurements. Finally, all data are entered and stored in a computerized data base system at the birth registry.This study included mothers who had at least single LBW baby followed by a subsequent birth before 2010. The inclusion criteria required all records to have a hospital number to enable linkage of mother with their respective siblings. We excluded all women with multiple gestations, those missing records on number of deliveries (i.e. whether singleton or multiples) and unknown child status , stillbirths and missing birth weight. The remaining 26,191 comprised the final sample size .The main outcome variable was LBW. LBW was defined as birth weight of less than 2500 grams. Recurrence of LBW was defined as repetition of LBW delivery in a subsequent pregnancy . IndepenData were analyzed using STATA version 13.1 . Numeric variables were summarized using mean (standard deviation) while comparison of means was performed using Student’s t-test. Multivariate log-binomial regression model was used to estimate the relative risk and recurrence risk of LBW with 95% confidence intervals (CIs). A robust variance estimator was used to account for correlation between births of the same mother. A p-value of less than 5% was considered statistically significant.Ethical approval was obtained from Kilimanjaro Christian Medical University College Research Ethics and Review Committee (CRERC) and the National Institute for Medical Research of Tanzania. Written informed consents were sought previously from all mothers during the interview. Both confidentiality and privacy were ensured where unique mother identification number were used instead of names while interviews were conducted in a separate room.There were 26,191 women who delivered at KCMC between 2000–2010, this corresponds to 30,800 deliveries. Out of these, 2,497 (9.5%) women had LBW infants in their first pregnancy. A total of 4,603 women confirmed to have more than one delivery within the follow up time, out of which 325 (7.1%) had recurrent LBW.Socio-demographic characteristics of 26,191 mothers in the first pregnancy are shown in In the multivariable analysis mothers who delivered LBW baby in the first pregnancy had over 5 times higher risk of having LBW in subsequent pregnancies , an absolute recurrence risk of 28.1%. Likewise, mothers who had less than four ANC visits , delivered a preterm baby in the first pregnancy , those with HIV positive status  and those who had preeclampsia  had significantly higher risk of delivering a LBW baby in subsequent pregnancies .We performed a stratified analysis by maternal characteristics in the first birth  adjusted for maternal BMI, Maternal age, and maternal education level in the first pregnancy . The higThe relative recurrence risk of LBW was higher among women with less than four antenatal care visits , those with ≥37 weeks of gestational , those with positive HIV status (RR:7.49: 3.91–14.36) and those without preeclampsia  in the first pregnancy as compared to women in the reference categories .This study explored the incidence of LBW, LBW recurrence and associated factors among women who delivered singletons in subsequent pregnancies. A total of 9.5% women had LBW baby in their first pregnancy. The incidence of LBW in subsequent pregnancy was 7.1% while the absolute risk of recurrence was 28.1%. Predictors of LBW in subsequent pregnancy included delivery of LBW baby in first pregnancy, less than 4 visits attendance to antenatal care, prematurity, HIV positive status of mother and preeclampsia.The percentage of LBW in this study is almost the same as the regional estimate (9.5%) but slightly higher than the national average (7%) which was previously reported by DHS . This esWomen with a previous history of LBW have been reported to have an increased risk of experiencing LBW in subsequent pregnancies , 24, 27.In the present study, ANC attendance was a strong predictor of recurrences of LBW. Higher recurrence risk among women with inadequate antenatal care has also previously been reported in Pelotas, Brazil . The higPreterm birth was found to be associated with over twice the risk of LBW recurrence in this study. Similar findings were also reported elsewhere , 16, 27.Although previous studies have establish the association between the recurrence risk of LBW by maternal demographic characteristics such as age, BMI, smoking status and parity , 27, 29,Incidence of LBW in subsequent pregnancy was 7.1% and the absolute risk of LBW recurrence in this population was 28.1% which is higher compared to 5.2% among those who delivered a normal birth weight baby. Recurrent LBW was associated with the history of LBW in first pregnancy, history of pre-eclampsia/ eclampsia, prematurity, inadequate antenatal care visits and HIV positive status of the mother. Identification of factors associated with LBW recurrence, proper post-partum care management to ensure Healthy Timing and Spacing of Pregnancy, Pre-conception care and close clinical follow-up during subsequent pregnancy may help reduce LBW recurrence.


What are the long-term results of multimodal treatment for adult attention-deficit/hyperactivity disorder (ADHD) when comparing cognitive behavioral group psychotherapy (GPT) with individual clinical management (CM) in combination with either methylphenidate or placebo?In this follow-up assessment of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a multicenter randomized clinical trial, 256 adults participated in follow-up 1.5 years after the intervention ended. The severity of ADHD symptoms improved in all 4 prior treatment groups, with no significant difference found between GPT and CM, but methylphenidate was associated with a larger improvement in symptoms compared with placebo.Results from the COMPAS trial demonstrate an improvement of ADHD symptoms over 1.5 years in adults with ADHD after 1 year of treatment with methylphenidate plus either GPT or CM. This follow-up assessment of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a multicenter randomized clinical trial, evaluates the long-term efficacy of multimodal treatment for attention-deficit/hyperactivity disorder (ADHD). Knowledge about the long-term effects of multimodal treatment in adult attention-deficit/hyperactivity disorder (ADHD) is much needed.To evaluate the long-term efficacy of multimodal treatment for adult ADHD.This observer-masked, 1.5-year follow-up of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), a prospective, multicenter randomized clinical trial, compared cognitive behavioral group psychotherapy (GPT) with individual clinical management (CM) and methylphenidate (MPH) with placebo . Recruitment started January 2007 and ended August 2010, and treatments were finalized in August 2011 with follow-up through March 2013. Overall, 433 adults with ADHD participated in the trial, and 256 (59.1%) participated in the follow-up assessment. Analysis began in November 2013 and was completed in February 2018.After 1-year treatment with GPT or CM and MPH or placebo, no further treatment restrictions were imposed.The primary outcome was change in the observer-masked ADHD Index of Conners Adult ADHD Rating Scale score from baseline to follow-up. Secondary outcomes included further ADHD rating scale scores, observer-masked ratings of the Clinical Global Impression scale, and self-ratings of depression on the Beck Depression Inventory.P = .48). The adjusted mean decreased to 13.8 for the MPH arm and 15.2 for the placebo arm . As in the core study, MPH was associated with a larger reduction in symptoms than placebo at follow-up. These results remained unchanged when accounting for MPH intake at follow-up. Compared with participants in the CM arm, patients who participated in group psychotherapy were associated with less severe symptoms as measured by the self-reported ADHD Symptoms Total Score according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) of Conners Adult ADHD Rating Scale  and in the subscale of reducing pure hyperactive symptoms, measured via the Diagnostic Checklist for the diagnosis of ADHD in adults . Regarding the Clinical Global Impression scale assessment of effectiveness, the difference between GPT and CM remained significant at follow-up . No differences were found for any comparison concerning depression as measured with the Beck Depression Inventory.At follow-up, 256 of 433 randomized patients  participated. Of the 256 patients participating in follow-up, the observer-masked ADHD Index of Conners Adult ADHD Rating Scale score was assessed for 251; the mean (SD) baseline age was 36.3 (10.1) years; 125 patients (49.8%) were men; and the sample was well-balanced with respect to prior randomization . At baseline, the all-group mean ADHD Index of Conners Adult ADHD Rating Scale score was 20.6, which improved to adjusted means of 14.2 for the GPT arm and 14.7 for the CM arm at follow-up with no significant difference between groups (difference, −0.5; 95% CI, −1.9 to 0.9; Results from COMPAS demonstrate a maintained improvement in ADHD symptoms for adults 1.5 years after the end of a 52-week controlled multimodal treatment period. The results indicate that MPH treatment combined with GPT or CM provides a benefit lasting 1.5 years. Confirming the results of the core study, GPT was not associated with better results regarding the primary outcome compared with CM.ISRCTN54096201isrctn.org Identifier:  Moreover, quality of evidence was evaluated as poor by a 2018 Cochrane review.6Although guidelines recommend multimodal treatments in attention-deficit/hyperactivity disorder (ADHD), evidence of long-lasting effects in adults is scarce.9 To assess the long-term effects of multimodal treatments, participants in COMPAS were reexamined 1.5 years after the interventions were terminated.To our knowledge, the Comparison of Methylphenidate and Psychotherapy Study (COMPAS) is the first, and so far largest, multicenter randomized clinical study that evaluates the effects of GPT compared with clinical management (CM) combined with methylphenidate (MPH) or placebo in adults with ADHD over a 1-year treatment period.7 Methylphenidate combined with GPT or CM yielded better results than placebo regarding the primary outcome 12 after 12 weeks of intensive treatment and during the maintenance phase after 1 year. Group psychotherapy was significantly associated with better results on the Clinical Global Impression (CGI) scale compared with CM.13In the core study, all treatment arms showed improvements in ADHD symptoms.16 Nevertheless, there is some evidence indicating a potential lasting effect of MPH even after discontinuation in adults.17 Huss et al18 found a 6-month enduring effect of long-acting MPH on symptoms of ADHD after discontinuation.The question of the long-term effects of MPH treatment is still open to debate. In natural settings, discontinuation rates in patients with ADHD are high.5; however, evidence of long-lasting effects is lacking.19 Given these considerations, this article analyzes long-term effects of multimodal treatments (GPT vs CM plus MPH or placebo) on ADHD symptoms in the 1.5-year follow-up of COMPAS.Psychological interventions are part of comprehensive treatment programs for ADHD20 as well as results of the core study (steps 1 and 2) have been reported previously.9Comparison of Methylphenidate and Psychotherapy Study is a 3-step factorial, multicenter randomized clinical trial. The trial protocol and statistical analysis plan are available in The core study comprised a 12-week intensive treatment followed by maintenance therapy over 9 months. Follow-up assessment (step 3) was conducted 2.5 years after baseline . The basCONSORT) reporting guideline.The COMPAS trial received approval from the leading ethics committee  and local ethics committees at each study site. It was authorized by relevant German authorities (EudraCT No.: 2006-000222-31). This report follows the Consolidated Standards of Reporting Trials  was included in the amendment of the trial protocol in 2009.Treatments ended after 52 weeks (T4).12 the Diagnostic Checklist for the diagnosis of ADHD in adults , and the CGI scale.13 The CGI scale comprises 3 global subscales  and assesses the global severity of illness and change in the clinical condition since baseline. To assess depressive symptoms, the Beck Depression Inventory (BDI-II)23 was used.Long-term efficacy was evaluated, including masked observer ratings and self-ratings of the CAARS ,Treatment allocation, including follow-up assessment, was masked at all times for interviewing raters. Comparison of Methylphenidate and Psychotherapy Study was double-masked for medication and open with respect to assignment to GPT and CM for patients and therapists.12 (CAARS-O:L) score from baseline (T1) to T5 and the stability of results from T4 (week 52) to T5. It further examines CAARS-O:L and self-ratings of CAARS (CAARS-S:L),12 ADHD-DC,21 CGI,13 and BDI-II.23This report focuses on changes in the observer-rated ADHD Index of CAARS24 as fixed covariates. Regression-based within-group means at T5 were calculated at the corresponding all-group baseline mean in the FAS, ie, the mean at T1 across all groups, to account for random baseline imbalances and for dropout at T5. Response measurements (binary) and CGI measurements  were analyzed in logistic and proportional odds models, respectively.As in the core study, analyses were conducted according to randomized treatment in the full analysis set (FAS). The statistical analysis plan appears in P values were 2-tailed and considered to be significant in an exploratory sense if less than .05. Programming was performed using SAS version 9.2 (SAS Institute) in UNIX.The primary focus of statistical analysis was on 2 × 2 comparisons of GPT vs CM and MPH vs placebo. Data description was done for the 4 randomized arms . The CAARS-O:L ADHD Index12 was assessed at follow-up for 251 participants. Among 433 randomized patients, a baseline was obtained from 419, constituting the FAS of the core study; 256 of these individuals participated in observer-masked ratings at follow-up . The adjusted mean decreased to 13.8 for the MPH arm and 15.2 for the placebo arm . A significant difference in the CAARS-O:L ADHD Index score at T5 was found between the group that was previously randomized to MPH compared with the group previously randomized to placebo , whereas the difference between GPT and CM was not significant  , indicating stable overall effects of randomized GPT vs CM and MPH vs placebo on ADHD symptoms at follow-up.At baseline, the all-group mean ADHD Index of Conners Adult ADHD Rating Scale score was 20.6, which improved to adjusted means of 14.2 for the GPT arm and 14.7 for the CM arm at follow-up with no significant difference between groups  . See eTaP = .06; no MPH at T5 for MPH vs placebo: AMD, −1.0; 95% CI, −2.6 to 0.7; P = .25; P value for interaction = .35). The mean difference in the CAARS ADHD Index between those taking MPH at T5 and those not taking it was numerically greater for those previously randomized to MPH compared with those randomized to placebo, reaching statistical significance for the MPH group .To explore how the CAARS ADHD Index was associated with MPH at T5 and randomized study medication, a further model including an interaction was calculated. The lowest mean CAARS ADHD Index score was found for patients taking MPH at T5 who had previously taken MPH . It was higher for patients previously randomized to the MPH arm but not taking MPH at T5  as well as for patients previously randomized to the placebo arm who were currently taking MPH . However, it was highest in the former placebo group not treated with MPH at T5 . Thus, the benefit of randomized MPH over placebo at follow-up was numerically larger for those who were taking MPH at T5 compared with those who were not. However, these effects of randomized medication on ADHD symptoms for the 2 groups with or without MPH at T5 as well as the difference between the effects were not statistically significant . The effect estimate of MPH vs placebo and GPT vs CM remained unchanged after adjustment.In an additional analysis, antidepressant intake at T5 was added to the initial model. Patients taking antidepressants scored 2.1 points  higher on the CAARS ADHD Index than patients not taking antidepressants . The results are depicted in 7The stability of the primary outcome scale from T4 to T5 was analyzed in a longitudinal linear model . The CAARS-S:L ADHD Index  (eTable 8 in 23 no differences were found for any comparison (eTable 7 in P = .03) from T4 to T5   . FurtherAge at baseline as a prognostic factor for outcomes at T5 showed no statistical significance. Age at baseline, sex, educational level, ADHD subtype, comorbidities, and severity at baseline were studied as potential moderators for outcomes at T5. However, no statistically significant effects were found for any of these (data not shown).9 Our study revealed several promising new findings. First, irrespective of combined treatment (MPH vs placebo and GPT vs CM), we found stable improvements for ADHD symptoms and general functioning 1.5 years after a structured 52-week randomized clinical trial. Second, our results show that both specific (GPT) and unspecific (CM) psychological interventions were significantly better when combined with MPH vs placebo. Third, 1.5 years after treatment finalization, we found that patients who were randomized to the MPH arm during the study period scored significantly better on the primary outcome CAARS-O:L ADHD Index compared with patients randomized to the placebo arm. This indicates the longest-lasting effect on ADHD symptoms observed for MPH after dosage discontinuation. Our results remained stable even after controlling for effects of current antidepressants and/or current MPH intake at follow-up.To our knowledge, COMPAS is the first trial to examine long-term multimodal treatment effects on adult ADHD symptoms, following the highest methodological standards for diagnostic, therapeutic, and assessment procedures.To investigate long-lasting effects of MPH on ADHD symptoms, the analysis put a certain emphasis on changes of observer and self-rating scales from T1 to T5 and the stability of results from T4 to T5. Analysis of changes from T4 to T5 for the CAARS-O:L ADHD Index revealed minor but insignificant declines for all study groups, indicating stable outcomes over a 1.5-year period.25 Its clinical effectiveness is thought to stop quickly after elimination.25 Explanation for long-lasting effects of multimodal treatment with MPH on ADHD symptoms may lie in neuroplasticity associated with learning processes26 as well as in coping strategies acquired during medication that outlast discontinuation. Patients treated with MPH might benefit more from GPT and CM even if the latter does not specifically address ADHD-related issues. Given that only 78 of 251 patients (31.1%) of the present sample took MPH at T5, it is conceivable that MPH acts as a sort of catalyzer and enables individuals to acquire new skills that allow long-lasting improvements of ADHD symptoms that supersede a continued treatment.At first glance, the long-lasting effects of MPH combined with GPT or CM on ADHD symptoms might be surprising. Methylphenidate has a short half-life and, depending on formulation, a maximum effective action of 7 to 12 hours.30 Moreover, changes in the neuroglial network,28 such as an increase in dendritic spine density, have been demonstrated.31 In the short term, MPH led to striatal gene expression changes in adolescent rats.27 The dopaminergic neurotransmission pathway is regarded as being crucially associated with ADHD,34 and MPH leads to augmented striatal dopamine availability.34 Continuous dopamine transporter blockade of MPH can lead to alterations in the brain, as a 2012 meta-analysis35 found an increased density of striatal dopamine transporters in patients who were previously treated with MPH as well as a lower density for drug-naive patients. Moreover, MPH is supposed to downregulate dopamine turnover in children and adolescents with ADHD.36 Therefore, the number of individuals previously treated with MPH has to be considered as an influencing factor for subsequent medical treatments. In our follow-up sample, most (207 [82.5%]) had been untreated with MPH prior to randomization.Evidence from animal research revealed the influence of MPH on neuronal remodeling in several brain regions.37 However, in our study, ADHD symptoms remained improved and stable for 1.5 years after termination of controlled treatment.Potential upregulation of dopamine transporters after long-term MPH treatment is discussed to be associated with an increase in ADHD symptoms while not taking medication.38 However, the cellular and molecular mechanisms influenced by MPH are still not completely understood, and further research is required. Nevertheless, the perception of potential adaptive brain changes after long-term MPH treatment is in line with MPH-associated effects on brain function39 and structure,40 which might be an explanation for long-term efficacy. Meta-analyses41 and neuroimaging studies42 reveal the association of MPH and age with normalization of brain structure anomalies, such as volume reductions, with smaller structural brain differences between individuals with and without ADHD, in which more participants were treated with psychostimulants. An association of psychostimulants with subcortical volume normalization has not been verified by a 2017 meta-analysis of cross-sectional observational data43 and a 2014 longitudinal study in children.44 In structural magnetic resonance imaging examinations linked to COMPAS, there was no evidence of gray matter volume loss; however, a trend toward cerebellar gray volume gains after 1 year of MPH treatment was found.45Beyond upregulation or downregulation of dopamine receptors, multiple components, such as the Wnt signal transduction pathways, seem to play a role in the long-term mechanisms of MPH.46 suggest that dose optimization in stimulant medication, which is recommended by several guidelines47 and performed in COMPAS, may enhance efficacy and safety. Moreover, there is evidence of a positive association of medical treatment duration with benefit in ADHD.49 However, the direct effects of individual dosage, treatment duration, and lasting effects on ADHD symptoms need to be clarified through future studies.Furthermore, data from 201718 COMPAS participants were evaluated under real-life conditions. Although MPH had not been approved as standardized therapy for adult ADHD in Germany until 2014, all participants were offered the opportunity to be transferred to specialists who would prescribe MPH off-label after T4. Nevertheless, the percentage of patients taking MPH at follow-up was only one-third and balanced between the 4 treatment groups. Furthermore, the rate of patients having individual psychological interventions after the core study can be regarded as low. All these results may indicate that patients felt sufficiently treated after the core study; this agrees with the previously reported moderate to high treatment satisfaction.50Unlike other studies we are aware of that also investigated long-term effects of MPH on ADHD symptoms,The significant association of MPH at T5 with the CAARS-O:L ADHD Index in the group randomized to MPH may indicate an MPH-linked long-lasting neuromodulation effect in a multimodal setting. In contrast, patients taking MPH at T5 without an MPH pretreatment period  had improved CAARS ADHD Index scores as well but without statistical significance.56 A 2018 meta-analysis on long-term efficacy of psychosocial treatments for adults with ADHD57 found evidence of sustained effects of ADHD-specific psychosocial treatment approaches on ADHD symptoms for at least 12 months.Current evidence on follow-up assessments of cognitive behavioral therapy (CBT) in adults with ADHD is limited in terms of sample size and shorter follow-up periods compared with COMPAS.DSM-IV ADHD Symptoms Total Score can be interpreted to be closely linked to the result that treatment with structured GPT was generally assessed to be more effective by patients (measured with the CGI assessment of effectiveness) compared with nonspecific counseling.50 This agrees with results in psychotherapy research for other disorders, such as depression.58In line with the main outcome of COMPAS, GPT showed no significant improvement compared with CM regarding the primary observer-rated outcome at follow-up. The better performance of participants in the GPT arm compared with participants in the CM arm for the self-rated 60 as well as in a 3-month follow-up after CBT in patients taking medication by Emilsson et al.51 These findings indicate that patients’ individual symptom assessment and functional improvement after psychosocial interventions might differ from observer-rated symptom severity in the long term.57At follow-up, CGI global assessment of effectiveness again favored GPT over CM. Improvements in the CGI scale were also reported in patients with ADHD as an effect of CBT in combination with medication compared with medication alone by Safren et al6 who reported an increase of self-rated treatment effects on the hyperactivity/impulsivity domain at follow-up. A reason for this may be that GPT led to a higher level of self-awareness and concurrent self-control or to more acceptance of hyperactivity as a part of ADHD symptoms, which in turn facilitates the implementation of coping strategies.61For reducing pure hyperactive symptoms, our long-term results indicate that GPT is associated with larger improvement than CM, which again is in line with the results of Lopez et al,8 The differences between the 4 treatment approaches studied are rather marginal. All 4 interventions resulted in a sound improvement for both the short and long run. Daily life functioning was not measured apart from the CGI scale.62 Also, we compared a highly structured group (GPT) with a less specific individual therapy (CM). On the one hand, CM was chosen as an active, nonpharmacological control condition to simulate general practice, representing a so-far insufficiently investigated area. On the other hand, there is evidence that individual therapy settings are more effective than group treatment57; thus, the presence of nonspecific factors derived from the different modalities could be a confounding variable.This study had limitations. Although a large sample of COMPAS participants (>250) was recruited for follow-up assessment, a considerable number of patients (177 [40.9%]) failed to participate. Nevertheless, psychosocial and clinical baseline characteristics of the subsample assessed were descriptively similar to those of the baseline participants.35In COMPAS, a 1.5-year lasting improvement of ADHD symptoms in adult patients with ADHD following 1 year of multimodal treatment was found, with a significant effect of MPH on ADHD symptoms 1.5 years after discontinuation after a 1-year controlled intake period in a multimodal setting. Our results confirm the requirement for reevaluation of MPH treatment during medication-free periods, as proposed by the National Institute for Health and Care Excellence guidelines. However, further trials are needed to investigate the causes of long-lasting effects of multimodal treatments and treatment components on ADHD symptoms. Especially adaptive brain response to MPH in randomized clinical trials with longitudinal functional imaging studies is required to clarify final brain modifications.


The surfactants found in aerosols seem to be relatively strong acids, compared with weaker acids such as the long-chain carboxylic acids previously proposed as atmospheric surfactants. Surfactants from the oxidation of organic materials (perhaps vegetation- or soil-derived) seem a likely source of these substances in the atmosphere.Surfactants in the atmosphere have several potential roles in atmospheric chemistry. They can form films on aqueous surfaces, which lowers the surface tension and possibly delays water evaporation and gaseous transportation across the aqueous interface. They can also increase the solubility of organic compounds in the aqueous phase. Recently, the decrease of surface tension in cloud growing droplets has been suggested as relevant to increases in the number of droplets of smaller size, potentially enhancing cloud albedo. Natural surfactants in the lung aid gas transfer and influence the dissolution rate of aerosol particles, so surfactants in atmospheric aerosols, once inhaled, may interact with pulmonary surfactants.Ambient aerosols were collected from the edge of Norwich, a small city in a largely agricultural region of England, and analysed for surfactants. Methylene blue, a conventional dye for detecting anionic surfactants, has been used as a colorimetric agent. The concentration of surfactants expressed as methylene blue active substances (MBAS) is in the range of 6–170 pmol m(air). A negative correlation with chloride aerosol indicates that these surfactants are probably not the well-known surfactants derived from marine spray. A more positive correlation with aerosol nitrate and gaseous NO