Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Negative parenting behaviour as a mediator of the effects of telephone-assisted self-help for parents of pharmacologically treated children with attention-deficit/hyperactivity disorder

A previous randomised controlled trial demonstrated the effects of a telephone-assisted self-help (TASH) intervention for parents of pharmacologically treated children with attention-deficit/hyperactivity disorder (ADHD) on ADHD symptoms, oppositional symptoms, functional impairment, and negative parenting behaviour (per-protocol analyses). In the current study, we examined whether changes in positive and negative parenting behaviour mediated the effects on symptoms and impairment. Parents in an enhancement group (n = 51) participated in a 12-month TASH intervention (eight booklets plus up to 14 telephone consultations) as an adjunct to routine clinical care, whereas parents in a waitlist control group (n = 52) received routine clinical care only. Parents completed measures of child symptoms, child functional impairment, and parenting behaviour at baseline, at 6 months, and at 12 months. The mediating effects of parenting behaviour were examined using regression analyses. Per-protocol analyses (n = 74) revealed a significant indirect intervention effect on functional impairment through negative parenting behaviour at 6 months as well as indirect intervention effects on oppositional symptoms and functional impairment through negative parenting behaviour at 12 months. The indirect effect on ADHD symptoms through negative parenting behaviour at 12 months just failed to reach significance. The analyses yielded no indirect intervention effects through positive parenting behaviour. The study provides some, albeit limited, support for the importance of changes in negative parenting behaviour to achieve changes in symptoms and functional impairment during parent training. In consideration of the inconsistent results of previous studies concerning the mediating role of positive and negative parenting behaviour, further research is required to better understand the mechanisms of change during parent training, also including other possible mediators like parenting stress and parental self-efficacy

Prediction of Educational Attainment and Occupational Functioning in Young Adults With a Childhood Diagnosis of ADHD: Results from the Cologne Adaptive Multimodal Treatment (CAMT) Study

Objective: This longitudinal study examined early predictors of educational attainment and occupational functioning in adults with a childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD). Method: Participants (n=70) of the Cologne Adaptive Multimodal Treatment (CAMT) Study were diagnosed with ADHD and received adaptive multimodal ADHD treatment during childhood. They were then followed through adolescence into adulthood. Results: Hierarchical regression analysis revealed that poor reading skill and externalizing behaviors in childhood were early predictors of educational and occupational difficulties in adulthood. The use of stimulant medication in childhood predicted lower high school achievement, probably because medication use was confounded by indication. The regression models improved when intelligence scores and/or externalizing behaviors, especially delinquency, assessed in adolescence were considered as additional predictors. Conclusion: Children with ADHD, who continue to show reading difficulties and externalizing behavior problems after initial treatment, are at risk for educational and occupational difficulties and may need additional support

Family relations and behavioral-emotional problems in adolescents - an analysis with the adolescent version of the Family Relations Test for Children and Adolescents

Objectives: So far hardly any instruments are available for the German-speaking countries, covering family relations from the perspective of young people reliably. Moreover, the relationship between family relations from the perspective of young people and behavioral problems has been rarely investigated. Method: Based on the Family Relations Test, which has been developed originally for children, the Family Relations Test for Children and Adolescents was developed in order to assess the family relations from the perspective of adolescents (94 items, 44 % newly developed). A clinical sample (n = 152) and a fi eld sample (n = 132) was tested with this instrument and additionally behavioural problems of the adolescents were rated by the parents and the adolescents. Results: The two-factor solution of the principal component analysis resulted in a clear distinction between two factors describing positive and negative family relations. The internal consistencies (Cronbach's Alpha) of the scales describing positive and negative relations are between.91 and.93. On these total scores young people from the clinic sample describe overall stronger negative relations in their families compared to young people in the fi eld sample. Within the clinic sample moderate correlations between the extent of mental problems of young people rated by themselves and their parents could be found. Conclusions: Positive and negative relationships of young people to the individual family members and to all members of the family as a whole can be assessed reliably and factorially valid. As expected, signifi cant correlations between negative family relations and mental problems could be found. The adolescent version of the Family Relations Test for Children and Adolescents proves to be a useful tool, to assess family relationships from the perspective of young people and thus to identify possible factors maintaining mental disorders of young people

Telephone-assisted self-help for parents of children with attention-deficit/hyperactivity disorder who have residual functional impairment despite methylphenidate treatment: a randomized controlled trial

BackgroundSelf-help parenting interventions have been shown to be effective in the management of children with attention-deficit/hyperactivity disorder (ADHD) and may be useful when there are barriers to face-to-face therapist-led parent trainings. Previous studies indicate that behavioral interventions might be a useful adjunct to medication in children with residual ADHD symptoms, and regarding comorbid oppositional symptoms and multiple domains of functional impairment. In the present study, we examined whether a telephone-assisted self-help (TASH) parenting behavioral intervention (written materials plus telephone counseling) enhanced the effects of methylphenidate treatment in children with ADHD. MethodsIn this randomized controlled trial, parents of 103 school-aged children with ADHD and residual functional impairment despite methylphenidate treatment were randomly assigned to either the enhancement group, which received the TASH intervention as adjunct to routine clinical care (including continued medication), or to the active control group, which received routine clinical care only (including continued medication). Parent-completed outcome measures at baseline and at 12months (postassessment) included functional impairment, ADHD symptoms, oppositional defiant disorder (ODD) symptoms, parenting behavior, and parental satisfaction with the intervention (ClinicalTrials.gov: NCT01660425; URL: ). ResultsIntention-to-treat analyses of covariance (ANCOVAs), which controlled for baseline data, revealed significant and moderate intervention effects for ODD symptoms and negative parenting behavior at the postassessment, whereas per-protocol analyses additionally showed significant and moderate effects on functional impairment (primary outcome). Parents expressed high satisfaction with the program. ConclusionsThe TASH program enhances effects of methylphenidate treatment in families who complete the intervention. Thediscontinuation rate of about 30% and comparison between completing and discontinuing families suggest that the program may be more suitable for families with a higher educational level and fewer additional stresses

Adaptive Multimodal Treatment for Children with Attention-Deficit-/Hyperactivity Disorder: An 18 Month Follow-Up

The Cologne Adaptive Multimodal Treatment (CAMT) study demonstrated that adaptive and individually tailored multimodal treatment for attention-deficit/hyperactivity disorder (ADHD) [consisting of behavior therapy (BT) and/or stimulant medication] is highly effective. This study reports findings of the 18 month follow-up assessment. Parents and teachers completed broad range behavior scales (Child Behavior Checklist/Teacher Report Form) and standardized ADHD and oppositional defiant disorder/conduct disorder symptom rating scales. Children that used medication to treat ADHD at follow-up (N = 32) and those that did not (N = 34) were analyzed separately. Parents did not report significant changes in child behavior from posttest to follow-up. Teacher ratings revealed some aggravation of ADHD symptoms in children that received medication, but this was not significant after Bonferroni correction. The initial advantage of combined treatment over BT was no longer evident. It can be concluded that treatment for ADHD that is tailored to the assessed needs of children results in large treatment effects that are maintained for at least 18 months

Long-Term Course After Adaptive Multimodal Treatment for Children With ADHD: An 8-Year Follow-Up

Objective: This study reassessed adolescents and young adults (15-22 years old) who received individually tailored multimodal treatment for ADHD (behavior therapy and/or stimulant medication) during childhood 6 to 12 years after treatment (M = 8.8 years, SD = 1.6). Method: All participants (N = 75) provided information about their social functioning. Most parents (83%) completed behavior rating scales. Results: Participants demonstrated significant improvement in behavior during the follow-up period with effect sizes on ADHD symptoms of d = 1.2 and 68% of the former patients in the normal range at follow-up. Participants reported elevated rates of grade retention (51%), school dropout (13%), special education service use (17%), school change (47%), and conviction (16%), but few were unemployed (4%). Conclusion: This study provides evidence that the effects of individually tailored multimodal treatment for ADHD in childhood are maintained into adolescence and young adulthood. No hints could be found that continued medication results in a more favorable long-term outcome

Efficacy of web-assisted self-help for parents of children with ADHD (WASH) - a three-arm randomized trial under field/routine care conditions in Germany

Background Current clinical guidelines recommend parent management training (PMT) in the treatment of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). However, (a) a lack of supply and (b) structural barriers to attending and continuing face-to-face PMT restrict the access to this training. The main purpose of this study is to investigate the efficacy of online PMT in decreasing ADHD symptoms and oppositional behavior problems and to evaluate the effects of additional telephone-based support of the parents. Methods The target sample size is n = 495 children with suspected or even clinical diagnosis of ADHD and current symptoms of ADHD or ODD. The study is based on a randomized three-arm parallel group design, in which the effects of treatment as usual (TAU) are compared to TAU plus web-assisted self-help (TAU+WASH) and to TAU plus web-assisted self-help and telephone-based support (TAU+WASH+SUPPORT). Discussion The results will provide important insights into the efficacy of web-assisted self-help for parents of children with ADHD and the additional effects of telephone-based support

Children with Attention-Deficit/Hyperactivity Disorder Grown Up: An 18-Year Follow-Up after Multimodal Treatment

Objective: ADHD treatment has positive effects on behavioral symptoms and psychosocial functioning, but studies that follow children treated for ADHD into adulthood are rare. Method: This follow-up study assessed symptom severity and functional outcomes of adults (n = 70) who had received individualized ADHD treatment in the Cologne Adaptive Multimodal Treatment (CAMT) Study at ages 6 to 10 years. Results: Despite symptomatic improvement, participants reported poorer educational and occupational outcomes than expected (e.g., currently unemployed: 17%). They had also been in contact with the justice system more often than expected (e.g., lifetime convictions: 33%) and were impaired on health-related outcomes (e.g., substance use problems: 15%). Several social outcomes were favorable (e.g., long-term relationship/married: 63%). Conclusion: Compared to the general population or norm samples, CAMT participants had a higher relative risk (RR) of functional impairments, demonstrating the need for continued support for a substantial proportion of the young adults

Behavioral Versus Nonbehavioral Guided Self-Help for Parents of Children With Externalizing Disorders in a Randomized Controlled Trial

Self-help interventions for parents, which have a behavioral basis, are considered to be an effective treatment option for children with externalizing disorders. Nonbehavioral approaches are widely used but have little empirical evidence. The main objective of this trial was to compare the efficacy of a behavioral and a nonbehavioral guided self-help program for parents. Families of children (aged 4-11 years) diagnosed with attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) were randomized to either a behavioral or a nonbehavioral guided self-help program including 8 parenting booklets and 10 counseling telephone calls. The analyses considered the ratings of 5 informants: blinded clinician, therapist, participant, (her or his) partner, and teacher. Of the 149 families randomized to treatment (intention-to-treat sample [ITT]), 110 parents completed the intervention (per-protocol sample [PP]). For the 4 primary outcome measures (blinded clinician- and participant-rated ADHD and ODD) at post assessment, the analysis revealed a treatment advantage for the behavioral group in blinded clinician-rated ODD symptoms (ITT: d = 0.37; PP: d = 0.35). Further treatment differences, all in favor of the behavioral group (ITT and PP), were detected in therapist ratings (i.e., ODD) and participant ratings (e.g., parental self-efficacy [only PP], negative parenting behavior, parental stress). In both samples, no differences were found at post-assessment for ratings of the partner and the teacher, or at the 12-month follow-up (only participant ratings available). Behavioral guided self-help shows some treatment advantage in the short term. No superiority over nonbehavioral therapy was detected 12 months after treatment termination