Emotion coaching skills as an augmentation to family-based therapy for adolescents with anorexia nervosa: A pilot effectiveness study with families with high expressed emotion.

OBJECTIVE: To examine the feasibility and acceptability of augmenting family-based treatment (FBT) for adolescents with anorexia nervosa (AN) or atypical anorexia nervosa (AAN) with a parent emotion coaching intervention (EC) focused on reducing parent expressed emotion. METHOD: In this pilot effectiveness trial, families of adolescents with AN/AAN exhibiting high expressed emotion received standard FBT with either (1) EC group or (2) support group (an attention control condition focused on psychoeducation). RESULTS: Forty-one adolescents with AN or AAN were recruited (88% female, Mage = 14.9 ± 1.6 years, 95% White: Non-Hispanic, 1% White: Hispanic, 1% Bi-racial: Asian). Most study adolescents were diagnosed with AN (59%) while 41% were diagnosed with AAN. Participating parents were predominantly mothers (95%). Recruitment and retention rates were moderately high (76% and 71%, respectively). High acceptability and feasibility ratings were obtained from parents and interventionists with 100% reporting the EC intervention was "beneficial"-"very beneficial." The FBT + EC group demonstrated higher parental warmth scores at post-treatment compared to the control group (standardized effect size difference, d = 1.58), which was maintained at 3-month follow-up. Finally, at post-treatment, the FBT + EC group demonstrated higher rates of full remission from AN/AAN (40%) compared to FBT + support (27%), and were nine times more likely to be weight restored by 3-month follow-up. DISCUSSION: Augmenting FBT with emotion coaching for parents with high expressed emotion is acceptable, feasible, and demonstrates preliminary effectiveness. PUBLIC SIGNIFICANCE: Family based treatment for AN/AAN is the recommended treatment for youth but families with high criticism/low warmth are less likely to respond to this treatment. Adding a parent emotion coaching group (EC) where parents learn to talk to their adolescents about tough emotions is feasible and well-liked by families.

An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism.

GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation.

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

Synthesis and photobiological evaluation of Ru(II) complexes with expanded chelate polypyridyl ligands.

Photoreactive Ru(II) complexes capable of ejecting ligands have been used extensively for photocaging applications and for the creation of "photocisplatin" reagents. The incorporation of distortion into the structure of the coordination complex lowers the energy of dissociative excited states, increasing the yield of the photosubstitution reaction. While steric clash between ligands induced by adding substituents at the coordinating face of the ligand has been extensively utilized, a lesser known, more subtle approach is to distort the coordination sphere by altering the chelate ring size. Here a systematic study was performed to alter metal-ligand bond lengths, angles, and to cause intraligand distortion by introducing a "linker" atom or group between two pyridine rings. The synthesis, photochemistry, and photobiology of five Ru(II) complexes containing CH2, NH, O, and S-linked dipyridine ligands was investigated. All systems where stable in the dark, and three of the five were photochemically active in buffer. While a clear periodic trend was not observed, this study lays the foundation for the creation of photoactive systems utilizing an alternative type of distortion to facilitate photosubstitution reactions.

Personality as a mediator of autistic traits and internalizing symptoms in two community samples.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by deficits in social functioning and is comorbid with internalizing disorders and symptoms. While personality is associated with these symptoms and social functioning in non-ASD samples, its role mediating the relationship between ASD traits and internalizing symptoms is not clear. METHODS: We studied the mediating effect of personality on the correlations between ASD traits and internalizing symptoms (i.e., depression, anxiety, stress) in two samples. Additionally, we explored the moderating effect of gender. Analyses were applied to a small (Study 1; N = 101) undergraduate sample. A broader sample recruited via an online crowdsourcing platform (Study 2; N = 371) was used to validate the results. RESULTS: Study 1's mediation analyses revealed that neuroticism was the only significant mediator. Study 2 replicated these results by finding extraversion to be an additional mediator for anxiety and extraversion, openness, and agreeableness as additional mediators for stress. Moderation analyses revealed that gender was never a significant moderator. CONCLUSIONS: These results support the effects of personality on the relationship between autism traits and internalizing symptoms. Future research should explore these effects in clinical samples to better understand the role of personality in symptomatology and the need to address it as part of intervention.

Pubertal Emergence of Testosterone Effects on Depressive Symptoms in Boys.

Background: Puberty-driven increases in the secretion of testosterone may be a biological factor that protects males against the development of depression. Although all males produce testosterone, there are substantial between-person differences that could contribute to differential vulnerability to depression among pre-adolescent and adolescent boys, particularly after pubertal onset. Indeed, experimental animal and human data have shown that low testosterone increases risk for depressive-like symptoms in males, whereas higher levels of testosterone may be protective; however, prior studies have primarily investigated these effects in adulthood. This study investigated whether lower circulating levels of testosterone predict depressive symptoms in pre-adolescent and adolescent boys, and in particular, whether the testosterone-depression association becomes prominent with advancing pubertal maturation. Methods: Male twins (N = 213; ages 10-15 years) from the Michigan State University Twin Registry self-reported their depressive symptoms and pubertal status using the Children's Depression Inventory and the Pubertal Development Scale, respectively. Salivary testosterone was assayed using high-sensitivity enzyme immunoassays. Mixed Linear Models (MLMs), which could account for the non-independence of twin data, were used for analyses. Results: As expected, lower testosterone concentrations were associated with higher depressive symptoms, and the magnitude of this effect increased with advancing pubertal status. In contrast, boys with higher levels of testosterone showed low levels of depressive symptomatology at all stages of pubertal maturation. Conclusions: Overall, these findings enhance understanding of within-sex variability in risk for depression in boys - average-to-high testosterone levels may underlie the general male resilience to depression after pubertal onset, whereas lower levels may increase vulnerability during/after puberty.

Autistic Traits Moderate Reappraisal Success for Depression and Anxiety Symptoms.

Cognitive reappraisal is associated with reduced emotional distress; however, little is known about the nature of this relationship in autism. This study tested whether autistic traits moderate reappraisal success (i.e., the negative correlation between reappraisal use and emotional symptom severity). Emotional symptoms were assessed using measures of depression, anxiety, and stress. It was hypothesized that more severe autistic traits would be associated with weaker reappraisal success across all scales. Data were collected from 377 adults using an on-line survey. Structural equation models found moderation effects for depression and anxiety, but not stress. Contrary to hypotheses, more severe autistic traits were associated with stronger reappraisal success. These preliminary results support including reappraisal in emotion regulation treatments for individuals with autistic traits.

Research Review: A meta-analysis of relapse rates in cognitive behavioral therapy for anxiety and related disorders in youth.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for youth with anxiety and related disorders, with a 59% remission rate at post-treatment. Results of reviews and meta-analyses indicate that treatment gains are maintained across long-term follow-up, at least in terms of symptom improvement. Less is known about relapse, defined as patients who initially achieve remission status but then experience a return of symptoms after a follow-up period. METHOD: The current study used meta-analysis to determine the overall rate of relapse in CBT for children and adolescents (age 18 years or younger) with anxiety and related disorders. Potential moderating factors of relapse rates, including demographic, methodological, and clinical/intervention characteristics, were also examined. Out of a pool of 78 abstracts, 13 full-text articles were retained for meta-analysis. An additional two articles were identified from other sources (total N = 535 patients). RESULTS: Results showed an overall relapse rate of 10.5% (including comorbid autism spectrum disorder) and 8% (excluding comorbid autism spectrum disorder) across studies. Moderator analyses demonstrated that relapse rates were higher among younger and more racially diverse samples, as well as among patients with comorbid externalizing disorders and those taking psychiatric medications. There were no differences in relapse rates as a function of primary diagnosis. CONCLUSIONS: Taken together, the findings indicate that relapse rates in CBT for anxious youth are relatively low, suggesting that treatment development and refinement efforts should focus on improving treatment response and remission rates for this population.

Biological Investigations of Ru(II) Complexes With Diverse ß-diketone Ligands.

The ß-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ2-O,O'-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ~ 30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ2-O,O'-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.

Avobenzone incorporation in a diverse range of Ru(II) scaffolds produces potent potential antineoplastic agents.

Four structurally distinct classes of polypyridyl ruthenium complexes containing avobenzone exhibited low micromolar and submicromolar potencies in cancer cells, and were up to 273-fold more active than the parent ligand. Visible light irradiation enhanced the cytotoxicity of some complexes, making them promising candidates for combined chemo-photodynamic therapy.

The dose-response curve in cognitive-behavioral therapy for anxiety disorders.

Previous studies examining the dose-response curve in psychotherapy have suggested that 11-19 sessions may be necessary for at least 50% of individuals to show clinically significant improvement. However, this curve has not been examined specifically for cognitive-behavioral therapy (CBT) for anxiety disorders, for which a more rapid recovery curve may be expected. Survival analysis was used to assess the dose-response curve for 201 patients with anxiety disorders who received weekly CBT at an anxiety specialty clinic. The primary outcome measure was the Outcome Questionnaire-45.2, which patients completed prior to each treatment session. Sixty-four percent of the sample achieved reliable change, and this response occurred in approximately five sessions on average. Fifty percent of the sample achieved clinically significant improvement, which occurred in approximately eight sessions on average. The findings suggest that earlier response may be expected in CBT for anxiety disorders, and are discussed in terms of potential ways to further improve response rates for this treatment.

Bis-tridentate N-Heterocyclic Carbene Ru(II) Complexes are Promising New Agents for Photodynamic Therapy.

Ruthenium(II) complexes developed for photodynamic therapy (PDT) are almost exclusively tris-bidentate systems with C2 or D3 symmetry. This is due to the fact that this structural framework commonly produces long-lived excited states, which, in turn, allow for the generation of large amounts of singlet oxygen (1O2) and other reactive oxygen species. Complexes containing tridentate ligands would be advantageous for biological applications as they are generally achiral (D2d or C2v symmetry), which eliminates the possibility of multiple isomers which could exhibit potentially different interactions with chiral biological entities. However, Ru(II) complexes containing tridentate ligands are rarely studied as candidates for photobiological applications, such as PDT, since they almost exclusively exhibit low quantum yields and very short excited-state lifetimes and, thus, are not capable of generating sufficient 1O2 or engaging in electron transfer reactions. Here, we report a proof-of-concept approach to make bis-tridentate Ru(II) complexes useful for PDT applications by altering their photophysical properties through the inclusion of N-heterocyclic carbene (NHC) ligands. Three NHC and two terpyridine ligands were studied to evaluate the effects of structural and photophysical modulations of bis-substituted Ru(II) complexes. The NHC complexes were found to have superior excited-state lifetimes, 1O2 production, and photocytotoxicity. To the best of our knowledge, these complexes are the most potent light-activated bis-tridentate complexes reported.

Toward Optimal Ru(II) Photocages: Balancing Photochemistry, Stability, and Biocompatibility Through Fine Tuning of Steric, Electronic, and Physiochemical Features.

Ru(II) complex photocages are used in a variety of biological applications, but the thermal stability, photosubstitution quantum yield, and biological compatibility of the most commonly used Ru(II) systems remain unoptimized. Here, multiple compounds used in photocaging applications were analyzed and found to have several unsatisfactory characteristics. To address these deficiencies, three new scaffolds were designed to improve key properties through modulation of a combination of electronic, steric, and physiochemical features. One of these new systems, containing the 2,2'-biquinoline-4,4'-dicarboxylic acid (2,2'-bicinchoninic acid) ligand, fulfills several of the requirements for an optimal photocage. Another complex, containing the 2-benzothiazol-2-yl-quinoline ligand, provides a scaffold for the creation of "dual action" agents.

Implementing an evidence-based psychological intervention for suicidal thoughts and behaviors on an inpatient unit: Process, challenges, and initial findings.

OBJECTIVE: Barriers to implementing evidence-based psychological treatments for suicidal thoughts and behaviors in busy hospital settings exist. Transdiagnostic interventions may serve to facilitate training in evidence-based treatment and more efficiently treat individuals with multiple psychiatric comorbidities. We describe the rationale for, process of, and initial data from implementing the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) on an inpatient unit for adults with suicidal thoughts and behaviors and affective disorders. METHOD: We analyzed clinical intake and outcome data from a subsample of patients admitted during the six months before and six months after UP implementation (n = 133 and n = 61, respectively), and available acceptability and fidelity data from the month following UP implementation. RESULTS: Patients improved significantly over the course of inpatient treatment before and after UP implementation. Effects for depression, suicidal ideation, anxiety, and emotion regulation were similar before and after UP implementation. Patients generally reported high acceptability of the UP and clinician fidelity to the protocol was variable during the month following UP implementation. CONCLUSIONS: The UP may be a promising evidence-based intervention for inpatient settings that treat individuals with suicidal thoughts and behaviors. Well-controlled, randomized trials are needed to determine efficacy, particularly regarding suicidal behavior after discharge.

Simulation of Drop-Size Distribution During Dropwise and Jumping Drop Condensation on a Vertical Surface: Implications for Heat Transfer Modeling.

Accurate models for condensation heat transfer are necessary to improve condenser design. Drop-size distribution is an important aspect of heat transfer modeling that is difficult to measure for small drop sizes. The present work uses a numerical simulation of condensation which incorporates the possibility of coalescence and coalescence-induced jumping over a range of drop sizes. Results of the simulation are compared with previous theoretical models and the impact of the assumptions used in those models is explored. In particular, previous drop-size distribution models may predict heat transfer rates less accurately for high contact angles and for coalescence-induced jumping since coalescence occurs over a range of drop sizes and does not always result in departure. The influence of various input parameters (nucleation site distribution approach, nucleation site density, contact angle, maximum drop size, heat transfer modeling to individual drops, and minimum jumping size) on the drop-size distribution and overall heat transfer rate is explored. Assignment of the nucleation site spatial distribution and heat transfer model affect both the drop-size distribution and predicted overall heat transfer rate. Results from the simulation suggest that, when the contact angle is large (as on superhydrophobic surfaces) and no coalescence-induced jumping occurs, the heat transfer may not be as sensitive to the maximum drop-size as previously supposed. Furthermore, this work suggests that when coalescence-induced jumping occurs, reducing the maximum drop size may not always increase heat transfer since drops similar in size to those removed by coalescence-induced jumping can contribute significantly to the overall heat transfer rate.

Cognitive and attentional vulnerability to depression in youth: A review.

Although depressive disorders are among the most common disorders in youth, highly efficacious treatments for childhood affective disorders are lacking. There is significant need to better understand the factors that contribute to the development and maintenance of depression in youth so that treatments can be targeted at optimal mechanisms. The aim of the current paper was to synthesize research on cognitive and neurobiological factors associated with youth depression, guided by De Raedt and Koster's model (2010) for vulnerability to depression in adults. Consistent with model predictions, there is evidence that attentional impairments are greatest in the context of negative information, relative to positive or neutral information, and some evidence that attentional deficits are associated with rumination in depressed youth. However, we found little evidence for the model's assumption that attentional bias is an etiological and maintenance factor for depression. There are several other model predictions that require additional study as current data are lacking. Overall, De Raedt and Koster's (2010) integrative cognitive and biological framework has tremendous potential to move the field forward in understanding the development of depression in youth. Additional longitudinal studies incorporating measures across biological and cognitive levels of analysis are needed.

Sleep duration differentially affects brain activation in response to food images in adolescents with overweight/obesity compared to adolescents with normal weight.

STUDY OBJECTIVES: Sleep is an important behavior that affects appetite and eating in adolescents. Our study examined food-related neural activation in brain regions associated with food reward and inhibition in adolescents under sleep-restricted and well-rested conditions. METHODS: In this within-subjects study, 52 adolescents (ages 12-18; 46% female; M age = 15.96 years, SD = 1.56) with normal weight (NW; N = 29, M body mass index % [BMI%] = 54.55, SD = 24.54) or overweight/obesity (OV/OB; N = 23, M BMI% = 93.78, SD = 4.60) spent 5 hours in bed at home each night for five consecutive nights and 9 hours in bed at home each night for 5 consecutive nights, with the first day of each condition occurring 4 weeks apart. The morning following each sleep modification period, functional magnetic resonance imaging (fMRI) data were collected while participants performed an inhibitory (go/no-go) task with food stimuli. RESULTS: We found significantly greater activation in brain regions associated with inhibition in adolescents with NW in response to food cues when sleep restricted. No increase in inhibition-related neural activation was observed in adolescents with OV/OB when sleep restricted. We also found neural activation consistent with greater reward processing associated with food cues following sleep restriction regardless of weight status. CONCLUSIONS: These findings suggest that chronic sleep restriction may increase the likelihood of suboptimal dietary behavior for adolescents with OV/OB because they do not experience increased inhibition-related neural responding to counter possible increased reward-related neural responding following sleep restriction.

Event-related potentials during sustained attention and memory tasks: Utility as biomarkers for mild cognitive impairment.

INTRODUCTION: The objective of the study is to validate attention and memory tasks that elicit event-related potentials (ERPs) for utility as sensitive biomarkers for early dementia. METHODS: A 3-choice vigilance task designed to evaluate sustained attention and standard image recognition memory task designed to evaluate attention, encoding, and image recognition memory were administered with concurrent electroencephalography acquisition to elicit ERPs in mild cognitive impairment (MCI) and healthy cohorts. ERPs were averaged, and mean or maximum amplitude of components was measured and compared between and within cohorts. RESULTS: There was significant suppression of the amplitude of the late positive potential in the MCI cohort compared with the healthy controls during 3-choice vigilance task, predominantly over occipital and right temporal-parietal region, and standard image recognition memory task over all regions. During standard image recognition memory task, diminished performance showed strong correlation with electroencephalography measurements. The old/new effects observed in the healthy controls cohort correlated with performance and were lost in MCI. DISCUSSION: ERPs obtained during cognitive tasks may provide a powerful tool for assessing MCI and have strong potential as sensitive and robust biomarkers for tracking disease progression and evaluating response to investigative therapeutics.

A transdiagnostic examination of decreased intolerance of uncertainty and treatment outcome.

Intolerance of uncertainty (IU) is characterized by negative beliefs and reactions to uncertainty. IU is present in emotional disorders and may be a mechanism of change in treatment . There are two components of IU, prospective and inhibitory IU, that may be differentially associated with outcome. The current study tested associations between pre- and post-treatment changes in the components of IU, symptoms of anxiety and depression, and treatment outcome in a large diagnostically heterogeneous partial hospital sample. Results suggested that social anxiety disorder was associated with greater pre-treatment prospective and inhibitory IU scores than those without the diagnosis. Results also showed that inhibitory IU predicted change in anxiety and depression symptoms and prospective IU and depression reductions predicted improvements in overall psychological health and psychological inflexibility. Only change in depression predicted improvement in interpersonal relationships throughout treatment. Clinical and theoretical implications of the findings are discussed.

Investigating the latent structure of distress intolerance.

Distress intolerance (DI) is defined as a perceived or actual inability to withstand distressing emotional or somatic states, which motivates the use of avoidance strategies. Despite widespread interest in DI, key questions about its underlying structure remain unanswered. The current study evaluated the latent structure of DI in two large samples using four-indicators and three taxometric procedures (MAMBAC, MAXEIG, and L-Mode). Data interpretation relied primarily on the Comparison Curve Fit Indices (CCFI). Overall, results from the three non-redundant procedures suggested that DI was more accurately characterized by a dimensional rather than a categorical conceptualization. Implications for assessment and conceptual models of DI are discussed.