Context Tourette disorder is a chronic and typically impairing childhood-onset neurological condition. Antipsychotic medications, the first-line treatments for moderate to severe tics, are often associated with adverse effects. Behavioral interventions, although promising, have not been evaluated in large-scale controlled trials. Objective To determine the efficacy of a comprehensive behavioral intervention for reducing tic severity in children and adolescents. Design, Setting, Participants Randomized, observer-blind, controlled trial of 126 youngsters recruited from December, 2004 through May, 2007 and aged 9–17 years with impairing Tourette or chronic tic disorder as primary diagnosis randomized to 8 sessions over 10 weeks of behavior therapy (n=61) or a control treatment consisting of supportive therapy and education (n=65). Responders received 3 monthly treatment booster sessions and were reassessed at 3- and 6-months post-treatment. Intervention Comprehensive behavioral intervention. Main Outcome Measures Yale Global Tic Severity Scale (range 0–40, score >15 indicating clinically significant tics), Clinical Global Impression-Improvement Scale (range 1-very much improved to 8-very much worse). Results Behavioral intervention led to a significantly greater decrease on the Yale Global Tic Severity Scale (24.7; CI:23.1,26.3) to 17.1 CI:15.1,19.1) from baseline to endpoint compared to the control treatment (24.6 CI:23.2,26.0) to 21.1 CI:19.2,23.0) (P<.001; 95% CI for difference between groups: 6.2, 2.0); (effect size=0.68). Compared to children in control treatment, significantly more children receiving behavioral intervention were rated as “very much” or “much improved” on the Clinical Global Impression-Improvement scale (52.5% to 18.5%, respectively; P<0.001; number-needed-to-treat=3). Attrition was low (12/126 or 9.5%); tic worsening was reported by 4% of children (5/126). Treatment gains were durable with 87% of available responders to behavior therapy showing continued benefit 6 months post-treatment. Conclusions A comprehensive behavioral intervention, compared with supportive therapy and education, resulted in greater improvement in symptom severity among children with Tourette and chronic tic disorder.

Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.

Although motor tics and/or vocal tics are the defining features of chronic tic disorder (CTD) and Tourette syndrome (TS), older youths and adults often report their tics to be preceded by an unpleasant sensation or "premonitory urge." While premonitory urge phenomena may play an important role in behavioral interventions for CTD/TS, standardized assessments for premonitory urges do not exist. The current study of 42 youths with TS or CTD presents initial psychometric data for a new, brief self-report scale designed to measure tic-related premonitory urges. Results showed that the Premonitory Urge for Tics Scale (PUTS) was internally consistent (alpha = .81) and temporally stable at 1 (r = 0.79, p < .01) and 2 (r = 0.86, p < .01) weeks. PUTS scores were also correlated with overall tic severity as measured by the Yale Global Tic Severity Scale (YGTSS; r = 0.31, p < .05) and the YGTSS number (r = 0.35, p < .05), complexity (r = 0.49, p < .01), and interference (r = 0.36, p < .05) subscales. Finally, an examination of the psychiatric correlates of the premonitory urge phenomenon yielded significant correlations between the PUTS and the Child Behavior Checklist (CBCL) anxiety/depression (r = 0.33, p < .05), and withdrawal (r = 0.38, p < .05) subscales as well as the Children's Yale-Brown Obsessive Compulsive Scale (CYBOCS; r = 0.31, p < .05). However, a cross-sectional examination of the data showed that the psychometric properties of the PUTS were not acceptable for youths 10 years of age and younger. Likewise, significant correlations found between the YGTSS subscales, CBCL subscales, CYBOCS, and the PUTS did not emerge in this younger age group. The clinical and theoretical implications of these findings are discussed.

Context Tics in Tourette syndrome begin in childhood, peak in early adolescence, and often decline by early adulthood. However, some adult patients continue to have impairing tics. Medications for tics are often effective but can cause adverse effects. Behavior therapy may offer an alternative but has not been examined in a large-scale controlled trial in adults. Objective To test the efficacy of a comprehensive behavioral intervention for tics in adults with Tourette syndrome of at least moderate severity. Design A randomized, controlled trial with posttreatment evaluations at 3 and 6 months for positive responders. Setting Three outpatient research clinics. Subjects Subjects (N = 122; 78 males, age 16 to 69 years) with Tourette syndrome or chronic tic disorder. Interventions Eight sessions of Comprehensive Behavioral Intervention for Tics or 8 sessions of supportive treatment delivered over 10 weeks. Subjects showing a positive response were given 3 monthly booster sessions. Main Outcome Measures Total Tic score of the Yale Global Tic Severity Scale and the Improvement scale of the Clinical Global Impression rated by a clinician blind to treatment assignment. Results Behavior therapy was associated with a significantly greater decrease on the Yale Global Tic Severity Scale (24.0 ± 6.47 to 17.8 ± 7.32) from baseline to endpoint compared to the control treatment (21.8 ± 6.59 to 19.3 ± 7.40) (P < .001; effect size = 0.57). Twenty-four of 63 subjects (38.1%) in CBIT were rated as Much Improved or Very Much Improved on the Clinical Global Impression-Improvement scale compared to 6.8% (4 of 63) in the control group (P < .0001). Attrition was 13.9% with no difference across groups. Subjects in behavior therapy available for assessment at 6 months posttreatment showed continued benefit. Conclusions Comprehensive behavior therapy is a safe and effective intervention for adults with Tourette syndrome.

Objective Pediatric obsessive-compulsive disorder (OCD) is a chronic, impairing condition associated with high levels of family accommodation (i.e., participation in symptoms). Understanding of factors that may engender accommodation of pediatric OCD is limited. This study conducted exploratory analyses of parent-, child-, and family-level correlates of family accommodation, considering both behavioral and affective components of the response. Method The sample included 65 youth (mean age = 12.3 years; 62% male) with OCD and their parents who completed a standardized assessment battery comprised of both clinical and self-report measures (e.g., CY-BOCS, Brief Symptom Inventory). Results Family accommodation was common, with the provision of reassurance and participation in rituals the most frequent practices (respectively occurring on a daily basis among 56% and 46% of parents). Total scores on the Family Accommodation Scale were not associated with child OCD symptom severity; however, parental involvement in rituals was associated with higher levels of child OCD severity and parental psychopathology, and with lower levels of family organization. Comorbid externalizing symptomatology and family conflict were associated with parent report of worse consequences when not accommodating. Conclusions Although these findings must be interpreted in light of potential Type I error, they suggest that accommodation is the norm in pediatric OCD. Family-focused interventions must consider the parent, child, and family-level variables associated with this familial response when teaching disengagement strategies.

Objective To examine the efficacy of exposure-based CBT plus a structured family intervention (FCBT) versus psychoeducation plus relaxation training (PRT) for reducing symptom severity, functional impairment, and family accommodation in youths with OCD. Methods Seventy-one 8–17 year old youngsters (mean 12.2 years, range 8–17, 37% male, 78% Caucasian) with primary OCD were randomized (70:30) to 12 sessions over 14 weeks of FCBT or PRT. Blind raters assessed outcomes with responders followed for six months to assess treatment durability. Results FCBT led to significantly higher response rates than PRT in ITT (57.1% vs 27.3%) and completer analyses (68.3% vs.35.3%). Using HLM, FCBT was associated with significantly greater change in OCD severity and child-reported functional impairment than PRT and marginally greater change in parent-reported accommodation of symptoms. These findings were confirmed in some, but not all, secondary analyses. Clinical remission rates were 42.5% for FCBT vs. 17.6% for PRT. Reduction in family accommodation temporally preceded improvement in OCD for both groups and child functional status for FCBT only. Treatment gains were maintained at 6-months. Conclusions FCBT is effective for reducing OCD severity and impairment. Importantly, treatment also reduced parent-reported involvement in symptoms with reduced accommodation preceding reduced symptom severity and functional impairment. Clinical Trials Registry Information Behavior Therapy for Children and Adolescents with Obsessive-Compulsive Disorder (OCD); http://www.clinicaltrials.gov; Unique Identifier: NCT00000386

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This article documents the development, factor structure, and psychometric properties of the parent- and youth-report forms of the Child Obsessive Compulsive Impact Scale-Revised (COIS-R), a measure of obsessive-compulsive disorder (OCD)-specific functional impairment. Using a sample of 250 youth (M age = 11.7, 54% male, 80% Caucasian) diagnosed with OCD in a university hospital-based child anxiety clinic, exploratory factor analysis was employed to develop a 4-factor structure for the parent-report measure (Daily Living Skills, School, Social, Family/Activities) and a 3-factor structure for the youth-report form (School, Social, Activities). Both measures demonstrated good internal consistency, concurrent validity, and test-retest reliability. Moreover, partial correlations demonstrated significant associations between COIS-R scales and clinician global assessment of functioning scores controlling for both symptom severity and comorbid internalizing and externalizing symptomatology. These findings suggest that the COIS-R may hold utility for assessing the specific impact of OCD symptoms on youth functioning.