A randomized controlled trial evaluating the effect of an internet-based cognitive-behavioral program on anxiety symptoms in a community-based sample of adolescents.

Adolescents' use of online resources to self-manage anxiety is growing. The objective of the current trial was to assess the effectiveness of an online, primarily self-led cognitive behavioral therapy (CBT) program in reducing anxiety symptoms compared to an active comparator, access to anxiety resources on a static website. A total of 563 adolescents (13-19 years) with self-identified anxiety concerns were enrolled. Self-reported anxiety symptoms were assessed pre- and post-intervention (6 weeks). Adolescents were further assessed 3 months post-intervention. Other outcomes assessed at the three time-points were quality of life (QOL) and healthcare utilization. Both interventions reduced anxiety symptoms after use. Group differences in symptom change were not significant post-intervention (p = 0.16), but were at 3 months (favouring online CBT; p = 0.04) with male participants reporting more symptom change (p = 0.03). Across time-points, as anxiety symptoms decreased, QOL increased (p < 0.001). Among participants that provided healthcare utilization before and after intervention use, the greatest changes in use were among online CBT users particularly for mental health provider visits (psychiatrist, -41.0 % vs. +18.5 %; social worker, -42.5 % vs. -22.1 %), hospital-based care (emergency department visits, -80.0 % vs. +79.4 %; hospital admissions, -76.1 % vs. +42.9 %), and use of self-help or alternative treatments (-60.0 % vs. +6.6 %). Results suggest that, over time, use of online CBT by adolescents can result in improved anxiety symptoms and fewer use of other healthcare resources compared to traditional online information seeking.

Evolution of Yin and Yang isoforms of a chromatin remodeling subunit precedes the creation of two genes.

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that de novo, beneficial alleles in the nurf-1 gene became fixed in two laboratory lineages of C. elegans after isolation from the wild in 1951, before methods of cryopreservation were developed. nurf-1 encodes an ortholog of BPTF, a large (>300 kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in C. elegans, nurf-1 has split into two, largely non-overlapping isoforms (NURF-1.D and NURF-1.B, which we call Yin and Yang, respectively) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of Caenorhabditis nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional nurf-1 transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional side products necessary to transcribe the Yin and Yang transcripts in the same cells. Our work demonstrates how gene sharing, through the production of multiple isoforms, can precede the creation of new, independent genes.

Mediators of Change in Capnometry Guided Respiratory Intervention for Panic Disorder.

Capnometry guided respiratory interventions have shown promising results in the treatment of panic disorder, but mechanisms of change are not yet well-understood. The current study examined changes in end-tidal carbon dioxide (ETCO2), anxiety sensitivity, and perceived control as mediators of panic symptom change. Sixty-nine adults with panic disorder received 4 weeks of respiratory training, and panic symptom severity and potential mediators were assessed at Pre-treatment, Mid-treatment, Post-treatment, 2-month follow-up, and 12-month follow-up. Multilevel mediation analyses showed that changes in perceived control significantly mediated changes in panic disorder severity and that for individuals who were hypocapnic at pre-treatment, ETCO2 was a significant mediator of symptom outcome. Findings provide further evidence that changes in perceived control, and improvements in respiratory dysregulation for hypocapnic individuals specifically, underlie symptom improvement from capnometry guided respiratory intervention for panic disorder.

A Multisite Benchmarking Trial of Capnometry Guided Respiratory Intervention for Panic Disorder in Naturalistic Treatment Settings.

Panic disorder (PD) is associated with hyperventilation. The efficacy of a brief respiratory feedback program for PD has been established. The aim of the present study was to expand these results by testing a similar program with more clinically representative patients and settings. Sixty-nine adults with PD received 4 weeks of Capnometry Guided Respiratory Intervention (CGRI) using Freespira, which provides feedback of end-tidal CO2 (PETCO2) and respiration rate (RR), in four non-academic clinical settings. This intervention is delivered via home use following initial training by a clinician and provides remote monitoring of client adherence and progress by the clinician. Outcomes were assessed post-treatment and at 2- and 12-month follow-up. CGRI was associated with an intent-to-treat response rate of 83% and a remission rate of 54%, and large decreases in panic severity. Similar decreases were found in functional impairment and in global illness severity. Gains were largely sustained at follow-up. PETCO2 moved from the slightly hypocapnic range to the normocapnic range. Benchmarking analyses against a previously-published controlled trial showed very similar outcomes, despite substantial differences in sample composition and treatment settings. The present study confirms prior clinical results and lends further support to the viability of CGRI in the treatment of PD.

Demonstrating test-retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response.

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test-retest reliability for the three electrophysiological measures selected for a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty-nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes-open and eyes-closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60-100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference-free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low-resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test-retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good-to-excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response.

Systematic review and meta-analysis of distraction and hypnosis for needle-related pain and distress in children and adolescents.

OBJECTIVE: To systematically review the evidence (and quality) for distraction and hypnosis for needle-related pain and distress in children and adolescents. To explore the effects of distraction characteristics (e.g., adult involvement, type of distracter), child age, and study risk of bias on treatment efficacy. METHODS: 26 distraction and 7 hypnosis trials were included and self-report, observer-report, and behavioral pain intensity and distress examined. Distraction studies were coded for 4 intervention characteristics, and all studies coded for child age and study risk of bias. RESULTS: Findings showed strong support for distraction and hypnosis for reducing pain and distress from needle procedures. The quality of available evidence was low, however. Characteristics of distraction interventions, child age, and study risk of bias showed some influence on treatment efficacy. CONCLUSIONS: Distraction and hypnosis are efficacious in reducing needle-related pain and distress in children. The quality of trials in this area needs to be improved.

The effects of mindful attention and state mindfulness on acute experimental pain among adolescents.

OBJECTIVE: Attention-based coping strategies for pain are widely used in pediatric populations. The purpose of this study was to test a novel mindful attention manipulation on adolescent's experimental pain responses. Furthermore, the relationship between state mindfulness and experimental pain was examined. METHODS: A total of 198 adolescents were randomly assigned to a mindful attention manipulation or control group prior to an experimental pain task. Participants completed measures of state mindfulness immediately prior to the pain task, and situational catastrophizing and pain intensity following the task. RESULTS: Overall the manipulation had no effect on pain. Secondary analysis showed that meditation experience moderated the effect of the manipulation. State mindfulness predicted pain outcomes, with reductions in situational catastrophizing mediating this relationship. CONCLUSIONS: The mindful attention manipulation was effective among adolescents with a regular meditation practice. State mindfulness was related to ameliorated pain responses, and these effects were mediated by reduced catastrophizing.

The role of trait mindfulness in the pain experience of adolescents.

UNLABELLED: Trait mindfulness appears to mitigate pain among adult clinical populations and has a unique relationship with pain catastrophizing. However, little is understood about this phenomenon among adolescents. The association between trait mindfulness and pain in both real-world and experimental contexts was examined in a community sample of adolescents. Participants were 198 adolescents who completed measures of trait mindfulness, pain catastrophizing, and pain interference, as well as an interview on day-to-day pain before undergoing an acute experimental pain task. Following the task, they provided ratings of pain intensity and state catastrophizing. Results showed that with regard to day-to-day pains, mindfulness was a significant and unique predictor of pain interference, and this relationship was partially mediated by pain catastrophizing. Mindfulness also had an indirect relationship with experimental pain intensity and tolerance. These associations were mediated by catastrophizing during the pain task. These findings highlight the association between trait mindfulness and both real-world and experimental pain and offer insight into how mindfulness may affect pain among youth. Findings are discussed in the context of current psychological models of pediatric pain and future avenues for research. PERSPECTIVE: This article highlights the association between trait mindfulness and pain variables among adolescents in both real-world and experimental pain settings. These findings offer further evidence of the unique relationship between trait mindfulness and pain catastrophizing in affecting pain variables across pain contexts and populations.

Psychological interventions for needle-related procedural pain and distress in children and adolescents.

BACKGROUND: This review is an updated version of the original Cochrane review published in Issue 4, 2006. Needle-related procedures are a common source of pain and distress for children. Our previous review on this topic indicated that a number of psychological interventions were efficacious in managing pediatric needle pain, including distraction, hypnosis, and combined cognitive behavioural interventions. Considerable additional research in the area has been published since that time. OBJECTIVES: To provide an update to our 2006 review assessing the efficacy of psychological interventions for needle-related procedural pain and distress in children and adolescents. SEARCH METHODS: Searches of the following databases were conducted for relevant randomized controlled trials (RCTs): Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; PsycINFO; the Cumulative Index to Nursing and Allied Health Literature (CINAHL); and Web of Science. Requests for relevant studies were also posted on various electronic list servers. We ran an updated search in March 2012, and again in March 2013. SELECTION CRITERIA: Participants included children and adolescents aged two to 19 years undergoing needle-related procedures. Only RCTs with at least five participants in each study arm comparing a psychological intervention group with a control or comparison group were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed trial quality and a third author helped with data extraction and coding for one non-English study. Included studies were coded for quality using the Cochrane Risk of bias tool. Standardized mean differences with 95% confidence intervals were computed for all analyses using Review Manager 5.2 software. MAIN RESULTS: Thirty-nine trials with 3394 participants were included. The most commonly studied needle procedures were venipuncture, intravenous (IV) line insertion, and immunization. Studies included children aged two to 19 years, with the most evidence available for children under 12 years of age. Consistent with the original review, the most commonly studied psychological interventions for needle procedures were distraction, hypnosis, and cognitive behavioural therapy (CBT). The majority of included studies (19 of 39) examined distraction only. The additional studies from this review update continued to provide strong evidence for the efficacy of distraction and hypnosis. No evidence was available to support the efficacy of preparation and information, combined CBT (at least two or more cognitive or behavioural strategies combined), parent coaching plus distraction, suggestion, or virtual reality for reducing children's pain and distress. No conclusions could be drawn about interventions of memory alteration, parent positioning plus distraction, blowing out air, or distraction plus suggestion, as evidence was available from single studies only. In addition, the Risk of bias scores indicated several domains with high or unclear bias scores (for example, selection, detection, and performance bias) suggesting that the methodological rigour and reporting of RCTs of psychological interventions continue to have considerable room for improvement. AUTHORS' CONCLUSIONS: Overall, there is strong evidence supporting the efficacy of distraction and hypnosis for needle-related pain and distress in children and adolescents, with no evidence currently available for preparation and information or both, combined CBT, parent coaching plus distraction, suggestion, or virtual reality. Additional research is needed to further assess interventions that have only been investigated in one RCT to date (that is, memory alteration, parent positioning plus distraction, blowing out air, and distraction plus suggestion). There are continuing issues with the quality of trials examining psychological interventions for needle-related pain and distress.

Usability testing of an online self-management program for adolescents with juvenile idiopathic arthritis.

BACKGROUND: A new bilingual (English and French) Internet-based self-management program, Teens Taking Charge: Managing Arthritis Online, for adolescents with arthritis and their parents was developed following a needs assessment. OBJECTIVES: This study explored the usability (user performance and satisfaction) of the self-management program for youth with juvenile idiopathic arthritis (JIA) and their parents to refine the health portal prototype. METHODS: A qualitative study design with semi-structured, audio taped interviews and observation by a trained observer was undertaken with two iterative cycles to determine the usability (ease of use, efficiency, errors, and user satisfaction) of the user interface and content areas of the intervention. A purposive sample of English-speaking (n = 11; mean age = 15.4, standard deviation [SD] 1.7) and French-speaking (n = 8; mean age = 16.0, SD 1.2) adolescents with JIA and one of their respective parents/caregivers were recruited from 2 Canadian tertiary care centers. Descriptive statistics and simple content analyses were used to organize data into categories that reflected the emerging usability themes. RESULTS: All of the participants had access to a computer/Internet at home; however, adolescents were more comfortable using the computer/Internet than their parents. Adolescents and parents provided similar as well as differing suggestions on how the website user interface could be improved in terms of its usability (navigation; presentation and control usage errors; format and layout; as well as areas for further content development). There were no major differences in usability issues between English- and French-speaking participants. Minor changes to the website user interface were made and tested in a second cycle of participants. No further usability problems were identified in the second iterative cycle of testing. Teens and parents responded positively to the appearance and theme of the website (ie, promoting self-management) and felt that it was easy to navigate, use, and understand. Participants felt that the content was appropriate and geared to meet the unique needs of adolescents with JIA and their parents as well as English- and French-speaking families. Many participants responded that the interactive features (discussion board, stories of hope, and video clips of youth with JIA) made them feel supported and "not alone" in their illness. CONCLUSIONS: We describe the usability testing of a self-management health portal designed for English- and French-speaking youth with arthritis and their parents, which uncovered several usability issues. Usability testing is a crucial step in the development of self-management health portals to ensure that the various end users (youth and parents) have the ability to access, understand, and use health-related information and services that are delivered via the Internet and that they are delivered in an efficient, effective, satisfying, and culturally competent manner.

Reduced brain responses to novel sounds in depression: P3 findings in a novelty oddball task.

There have been conflicting findings as to whether the P3 brain potential to targets in oddball tasks is reduced in depressed patients. The P3 to novel distracter stimuli in a three-stimulus oddball task has a more frontocentral topography than P3 to targets and is associated with different cognitive operations and neural generators. The novelty P3 potential was predicted to be reduced in depressed patients. EEG was recorded from 30 scalp electrodes (nose reference) in 20 unmedicated depressed patients and 20 matched healthy controls during a novelty oddball task with three stimuli: infrequent target tones (12%), frequent standard tones (76%) and nontarget novel stimuli, e.g., animal or environment sounds (12%). Novel stimuli evoked a P3 potential with shorter peak latency and more frontocentral topography than the parietal-maximum P3b to target stimuli. The novelty P3 was markedly reduced in depressed patients compared to controls. Although there was a trend for patients to also have smaller parietal P3b to targets, this group difference was not statistically significant. Nor was there a group difference in the earlier N1 or N2 potentials. The novelty P3 reduction in depressed patients is indicative of a deficit in orienting of attention and evaluation of novel environmental sounds.

The Fear of Positive Evaluation Scale: psychometric properties in a clinical sample.

Cognitive models of social anxiety suggest that fear of negative evaluation (FNE) is the central cognitive dimension underlying the disorder. The Fear of Positive Evaluation Scale (FPES; Weeks, Heimberg, & Rodebaugh, 2008) was recently developed to assess an additional cognitive dimension purported to underlie social anxiety disorder (SAD), but its psychometric properties have yet to be examined in clinical populations. The present study, with 133 treatment-seeking patients, examined the applicability of the FPES with a clinical sample. Results indicated that the FPES was factorially distinct from a measure assessing FNE, and patients with SAD (n=51) had higher mean scores on the FPES than patients with other anxiety disorders (n=82). The FPES also showed adequate reliability (internal consistency), good convergent and discriminant validity, acceptable criterion-related validity in predicting social interaction anxiety symptoms, and appropriate sensitivity to treatment. The FPES appears to have good psychometric properties and is a promising new assessment tool for better understanding SAD.

A systematic review of randomized controlled trials examining psychological interventions for needle-related procedural pain and distress in children and adolescents: an abbreviated cochrane review.

OBJECTIVE: To report the results of a systematic review of randomized controlled trials (RCTs) of psychological interventions for children and adolescents undergoing needle-related procedures. METHODS: A variety of cognitive-behavioral psychological interventions for managing procedural pain and distress in children and adolescents between 2 and 19 years of age were examined. Outcome measures included pain and distress as assessed by self-report, observer report, behavioral/observational measures, and physiological correlates. RESULTS: Twenty-eight trials met the criteria for inclusion in the review and provided the data necessary for pooling the results. Together, the trials included 1,039 participants in treatment conditions and 951 in control conditions. The largest effect sizes for treatment improvement over control conditions were found for distraction, combined cognitive-behavioral interventions, and hypnosis, with promising but limited evidence for several other psychological interventions. CONCLUSIONS: Recommendations for conducting future RCTs are provided, and particular attention to the quality of trial design and reporting is highlighted.

A phospho-signaling pathway controls the localization and activity of a protease complex critical for bacterial cell cycle progression.

Temporally and spatially controlled master regulators drive the Caulobacter cell cycle by regulating the expression of >200 genes. Rapid clearance of the master regulator, CtrA, by the ClpXP protease is a critical event that enables the initiation of chromosome replication at specific times in the cell cycle. We show here that a previously unidentified single domain-response regulator, CpdR, when in the unphosphorylated state, binds to ClpXP and, thereby, causes its localization to the cell pole. We further show that ClpXP localization is required for CtrA proteolysis. When CpdR is phosphorylated, ClpXP is delocalized, and CtrA is not degraded. Both CtrA and CpdR are phosphorylated via the same CckA histidine kinase phospho-signaling pathway, providing a reinforcing mechanism that simultaneously activates CtrA and prevents its degradation by delocalizing the CpdR/ClpXP complex. In swarmer cells, CpdR is in the phosphorylated state, thus preventing ClpXP localization and CtrA degradation. As swarmer cells differentiate into stalked cells (G1/S transition), unphosphorylated CpdR accumulates and is localized to the stalked cell pole, where it enables ClpXP localization and CtrA proteolysis, allowing the initiation of DNA replication. Dynamic protease localization mediated by a phospho-signaling pathway is a novel mechanism to integrate spatial and temporal control of bacterial cell cycle progression.

Placebo-controlled trial of dehydroepiandrosterone (DHEA) for treatment of nonmajor depression in patients with HIV/AIDS.

OBJECTIVE: Subsyndromal major depressive disorder is common among HIV-positive adults. This study was designed to assess the efficacy of dehydroepiandrosterone (DHEA) as a potential treatment. METHOD: One hundred forty-five patients with subsyndromal depression or dysthymia were randomly assigned to receive either DHEA or placebo; 90% (69 of 77) of the DHEA patients and 94% (64 of 68) of the placebo patients completed the 8-week trial. The primary measure of efficacy was a Clinical Global Impression improvement rating of 1 or 2 (much or very much improved) plus a final Hamilton Depression Rating Scale score

The efficacy and efficiency of a self-administered treatment for adolescent migraine.

Migraine headaches are frequent in adolescents. Although many adolescents are adequately treated palliatively with analgesics, an important subgroup requires prophylactic treatment. Medical treatments for adolescents with frequent severe headaches is often problematic. Prophylactic pharmacological treatments are often shunned by adolescents and their parents because of concern over drug usage. Moreover, propranolol, the most widely used prophylactic drug with adults, is frequently not effective. Psychological interventions are effective but are costly and often not available. A randomized controlled trial was undertaken to evaluate the efficacy and efficiency of a predominantly self-administered treatment that could be delivered in a very cost-efficient format. Eighty seven adolescents (63 females and 24 males) ranging in age from 11 to 18 years were randomly assigned to receive a self-administered treatment, the same treatment delivered by a therapist or a control treatment. Self-administered and clinic treatment were equally effective and superior to the control treatment. However, the self-administered treatment was substantially more efficient. Both active treatments were durable at 1-year follow-up.

Cognitive and relaxation treatment of paediatric migraine.

The present study compared the efficacy of two active treatments, relaxation training and cognitive coping, with a non-specific placebo control in the treatment of 42 children and adolescents with migraine. The first treatment is a simplified version of progressive deep muscle relaxation; the second, a form of cognitive restructuring involving the alteration of dysfunctional thought processes. The results demonstrated that each active treatment was superior to the non-specific intervention in reducing overall headache activity and frequency but not duration or intensity. There were no differences between the experimental groups, and both continued to improve through a 16-week follow-up period, but the control group did not. Initial level of headache severity was an important factor in treatment outcome, with children with severe headaches responding better than those with milder headaches. Possible reasons for the differential treatment effects are discussed, and the implications for future research are considered.