BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595.FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Background Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. Objective Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. Methods We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. Results Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FcεRI-mediated proximal and distal signaling, as well as reduced degranulation. Conclusion This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others.

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Interspersed requests are simple commands, with a high likelihood of being followed correctly, that are interspersed among instructional trials to increase the probability that a learner will attempt to perform new or difficult tasks without engaging in aggression or self-injurious behavior. This report presents two assessments of the effect of interspersed requests on aggression and self-injury during instruction. The participants were individuals with severe mental retardation who used aggression and self-injury to avoid difficult instructional situations. Results from both studies indicate that interspersed requests were effective at increasing the responsiveness of the learners to instructions and reducing levels of aggression and self-injury.

The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.

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The use of self-help interventions for parents of children with behaviour problems is becoming more prevalent. This review critically evaluated the evidence supporting the efficacy of such programmes for children with behaviour problems. Using a systematic literature search, two modes of delivery were evaluated, namely bibliotherapy and multimedia. Programmes that included minimal therapist support were also included. Overall, there is good evidence supporting the efficacy of self-help programmes in improving child behaviour, over the short and longer term. Self-help programmes led to outcomes similar to those achieved with more intensive therapist input. Including minimal levels of therapist support in addition to self-help materials enhances child and parent outcomes. Parents view self-help favourably but significantly less so than programmes including some form of therapist input. The future directions for self-help parent programmes include the need for longer-term follow-ups, the identification of moderators of outcome and economic evaluations of self-help programmes.

The efficacy of a self-help parent training programme for children with attention deficit hyperactivity disorder (ADHD) was evaluated. The New Forest Parenting Programme Self-help (NFPP-SH) is a 6-week written self-help psychological intervention designed to treat childhood ADHD. Forty-three children were randomised to either NFPP-SH intervention or a waiting list control group. Outcomes were child ADHD symptoms measured using questionnaires and direct observation, self-reported parental mental health, parenting competence, and the quality of parent-child interaction. Measures of child symptoms and parental outcomes were assessed before and after the intervention. ADHD symptoms were reduced, and parental competence was increased by self-help intervention. Forty-five percent of intervention children showed clinically significant reductions in ADHD symptoms. Self-help intervention did not lead to improvements in parental mental health or parent-child interaction. Findings provide support for the efficacy of self-help intervention for a clinical sample of children with ADHD symptoms. Self-help may provide a potentially cost-effective method of increasing access to evidence-based interventions for clinical populations.