Parent training for preschool ADHD: a randomized controlled trial of specialized and generic programs

BackgroundThe New Forest Parenting Package' (NFPP), an 8-week home-based intervention for parents of preschoolers with attention-deficit/hyperactivity disorder (ADHD), fosters constructive parenting to target ADHD-related dysfunctions in attention and impulse control. Although NFPP has improved parent and laboratory measures of ADHD in community samples of children with ADHD-like problems, its efficacy in a clinical sample, and relative to an active treatment comparator, is unknown. The aims are to evaluate the short- and long-term efficacy and generalization effects of NFPP compared to an established clinic-based parenting intervention for treating noncompliant behavior [Helping the Noncompliant Child' (HNC)] in young children with ADHD. MethodsA randomized controlled trial with three parallel arms was the design for this study. A total of 164 3-4-year-olds, 73.8% male, meeting DSM-IV ADHD diagnostic criteria were randomized to NFPP (N=67), HNC (N=63), or wait-list control (WL, N=34). All participants were assessed at post-treatment. NFPP and HNC participants were assessed at follow-up in the next school year. Primary outcomes were ADHD ratings by teachers blind to and uninvolved in treatment, and by parents. Secondary ADHD outcomes included clinician assessments, and laboratory measures of on-task behavior and delay of gratification. Other outcomes included parent and teacher ratings of oppositional behavior, and parenting measures. (Trial name: Home-Based Parent Training in ADHD Preschoolers; Registry: ClinicalTrials.gov Identifier: NCT01320098; URL: ). ResultsIn both treatment groups, children's ADHD and ODD behaviors, as well as aspects of parenting, were rated improved by parents at the end of treatment compared to controls. Most of these gains in the children's behavior and in some parenting practices were sustained at follow-up. However, these parent-reported improvements were not corroborated by teacher ratings or objective observations. NFPP was not significantly better, and on a few outcomes significantly less effective, than HNC. ConclusionsThe results do not support the claim that NFPP addresses putative dysfunctions underlying ADHD, bringing about generalized change in ADHD, and its underpinning self-regulatory processes. The findings support documented difficulties in achieving generalization across nontargeted settings, and the importance of using blinded measures to provide meaningful assessments of treatment effects

Study protocol for a randomized controlled trial comparing the efficacy of a specialist and a generic parenting programme for the treatment of preschool ADHD

BACKGROUND: The New Forest Parenting Programme (NFPP) is a home-delivered, evidence-based parenting programme to target symptoms of attention-deficit/hyperactivity disorder (ADHD) in preschool children. It has been adapted for use with 'hard-to-reach' or 'difficult-to-treat' children. This trial will compare the adapted-NFPP with a generic parenting group-based programme, Incredible Years (IY), which has been recommended for children with preschool-type ADHD symptoms.METHODS/DESIGN: This multicentre randomized controlled trial comprises three arms: adapted-NFPP, IY and treatment as usual (TAU). A sample of 329 parents of preschool-aged children with a research diagnosis of ADHD enriched for hard-to-reach and potentially treatment-resistant children will be allocated to the arms in the ratio 3:3:1. Participants in the adapted-NFPP and IY arms receive an induction visit followed by 12 weekly parenting sessions of 1½ hours (adapted-NFPP) or 2½ hours (IY) over 2.5 years. Adapted-NFPP will be delivered as a one-to-one home-based intervention; IY, as a group-based intervention. TAU participants are offered a parenting programme at the end of the study. The primary objective is to test whether the adapted-NFPP produces beneficial effects in terms of core ADHD symptoms. Secondary objectives include examination of the treatment impact on secondary outcomes, a study of cost-effectiveness and examination of the mediating role of treatment-induced changes in parenting behaviour and neuropsychological function. The primary outcome is change in ADHD symptoms, as measured by the parent-completed version of the SNAP-IV questionnaire, adjusted for pretreatment SNAP-IV score. Secondary outcome measures are: a validated index of behaviour during child's solo play; teacher-reported SNAP-IV (ADHD scale); teacher and parent SNAP-IV (ODD) Scale; Eyberg Child Behaviour Inventory - Oppositional Defiant Disorder scale; Revised Client Service Receipt Inventory - Health Economics Costs measure and EuroQol (EQ5D) health-related quality-of-life measure. Follow-up measures will be collected 6 months after treatment for participants allocated to adapted-NFPP and IY.DISCUSSION: This trial will provide evidence as to whether the adapted-NFPP is more effective and cost-effective than the recommended treatment and TAU. It will also provide information about mediating factors (improved parenting and neuropsychological function) and moderating factors (parent and child genetic factors) in any increased benefit.TRIAL REGISTRATION: Current Controlled Trials, ISRCTN39288126.</p

A self-help version of the New Forest Parenting Programme for parents of children with attention deficit hyperactivity disorder:a qualitative study of parent views and acceptability

Background Although parent interventions are recommended as a frontline treatment approach for children with attention deficit hyperactivity disorder (ADHD), a number of practical and situational barriers can impact accessibility and availability. Self-help parent interventions offer a potential alternative to therapist-led interventions when barriers prevent access to face-to-face treatment. This qualitative study aims to explore participant views and acceptability of self-help parent interventions. Method Semi-structured interviews were conducted with parents/carers of 12 children (age 6–10 years) with ADHD who received the self-help version of the New Forest Parenting Programme (NFPP-SH) as part of a randomised controlled trial. Thematic analysis (as proposed by Braun and Clarke) was used to analyse the data. Results Overall, participants had favourable views of the self-help intervention but also experienced some barriers to treatment adherence. Six key themes were identified in parent interviews related to parental desire to learn more; acquisition of new skills; the flexibility of the intervention; self-help intervention vs. traditional therapist-led formats; barriers to engagement in the home environment; and need for earlier access to help. Conclusions NFPP-SH was an acceptable intervention for parents. However, some parents may need additional support to overcome barriers associated with completing an intervention at home. Implications for healthcare providers and researchers developing self-help parent interventions for ADHD and child behaviour are discussed

Preschool hyperactivity specifically elevates long-term mental health risks more strongly in males than females: a prospective longitudinal study through to young adulthood

Evidence of continuities between preschool hyperactivity and adult mental health problems highlight the potential value of targeting early identification and intervention strategies. However, specific risk factors are currently unclear. This large-scale prospective longitudinal study aimed to identify which hyperactive preschoolers are at greatest long-term risk of poor mental health. One hundred and seventy children (89 females) rated as hyperactive by their parents and 88 non-hyperactive controls (48 females) were identified from a community sample of 4,215 3 year-olds. Baseline data relating to behavioral/emotional problems and background characteristics were collected. Follow-up mental health and functional impairment outcomes were collected between 14 and 25 years of age. At age 3 years, males and females in the hyperactive group had similarly raised levels of hyperactivity and other behavior problems. In adolescence/young adulthood, these individuals showed elevated symptoms of ADHD, conduct disorder, mood disorder, anxiety and autism, as well as functional impairment. Preschool hyperactivity was strongly predictive of poor adolescent/adult outcomes for males across domains with effects being specifically driven by hyperactivity. For females, the effects of preschool hyperactivity were smaller and dropped to non-significant levels when other preschool problems were taken into account. Environmental risk factors also differed between the sexes, although these may also have been mediated by genetic risk. In conclusion, these results demonstrate marked sex differences in preschool predictors of later adolescent/adult mental health problems. Future research should include a measure of preschool inattention as well hyperactivity. The findings highlight the potential value of tailored approaches to early identification strategies

A comparison of the clinical effectiveness and cost of specialised individually-delivered parent training for preschool attention-deficit/hyperactivity disorder and a generic, group-based programme: a multi-centre, randomised controlled trial of the New Forest Parenting Programme versus Incredible Years

Objective: To compare the efficacy and cost of specialised individually-delivered parent training (PT) for preschool children with attention-deficit/ hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). Design: Multi-centre, three-arm parallel group randomised controlled trial. Research Setting: National Health Service Trusts. Participants: Preschool children (33-54 months) fulfilling ADHD research diagnostic criteria. Interventions: New Forest Parenting Programme (NFPP) – 12 week individual, home-delivered ADHD PT programme; Incredible Years (IY) – 12 week group-based, PT programme initially designed for children with behaviour problems. Main outcome measures: Primary outcome - Parent ratings of child’s ADHD symptoms (Swanson, Nolan & Pelham Questionnaire - SNAP-IV). Secondary outcomes - teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post-treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputation). Intervention and other costs were estimated using standardized approaches. Results: NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms (mean difference -0.009 95%CI [-0.191, 0.173], p=0.921) or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms (-0.189 95%CI [-0.380, 0.003], p=0.053). NFPP significantly reduced parent-rated conduct-problems compared to TAU across scales (p-values.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1,591 versus £2,103). Conclusions: Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually-delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches. Funding: National Institute of Health Research. Trial Registration: Trial name: COPPI Trial; ISRCTN39288126

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570