Effects of High- versus Low-Intensity Clinician Training on Implementation of Family-Focused Therapy for Youth with Mood and Psychotic Disorders.

The implementation of evidence-based psychotherapies often requires significant commitments of time and expense from mental health providers. Psychotherapy protocols with rapid and efficient training and supervision requirements may have higher levels of uptake in publicly funded clinics. Family-focused therapy (FFT) is a 4-month, 12-session treatment for bipolar and psychosis patients consisting of psychoeducation, communication training, and problem-solving skills training. In a pilot randomized trial, we compared two methods of training community clinicians in FFT: (a) high intensity (n = 24), consisting of a 6-hour in-person didactic workshop followed by telephone supervision for every session with training cases; or (b) low-intensity training (n = 23), consisting of a 4-hour online workshop covering the same material as the in-person workshop followed by telephone supervision after every third session with training cases. Of 47 clinician participants, 18 (11 randomly assigned to high intensity, 7 to low) enrolled 34 patients with mood or psychotic disorders (mean age 16.5 ± 2.0 years; 44.1% female) in an FFT implementation phase. Expert supervisors rated clinicians' fidelity to the FFT manual based on taped family sessions. We detected no differences in fidelity scores between clinicians in the two training conditions, nor did patients treated by clinicians in high- versus low-intensity training differ in end-of-treatment depression or mania symptoms. Levels of parent/offspring conflict improved in both conditions. Although based on a pilot study, the results suggest that low-intensity training of community clinicians in FFT is feasible and can result in rapid achievement of fidelity benchmarks without apparent loss of treatment efficacy.

La implementación de psicoterapias factuales generalmente exige compromisos significativos de tiempo y gastos por parte de los profesionales de salud mental. Los protocolos de psicoterapia con los requisitos de capacitación y supervisión rápidas y eficaces pueden tener niveles más altos de captación en las clínicas financiadas con fondos públicos. La terapia centrada en la familia es un tratamiento de 4 meses y 12 sesiones para pacientes bipolares y con psicosis que consiste en psicoeducación, capacitación en comunicación y capacitación en habilidades de resolución de problemas. En un ensayo aleatorizado piloto, comparamos dos métodos de capacitar a profesionales clínicos de la comunidad en terapia centrada en la familia: (a) la capacitación de alta intensidad (n = 24), que consiste en un taller didáctico presencial de seis horas seguido de supervisión telefónica para cada sesión con casos de capacitación; o (b) la capacitación de baja intensidad (n=23), que consiste en un taller virtual de cuatro horas y cubre el mismo material que el taller presencial seguido de supervisión telefónica después de cada tercera sesión con casos de capacitación. De 47 profesionales clínicos participantes, 18 (11 asignados aleatoriamente a alta intensidad, y 7 a baja intensidad) inscribieron a 34 pacientes con trastornos del estado de ánimo o psicóticos (edad promedio 16.5+2.0 años; el 44.1 % mujeres) en una fase de implementación de la terapia centrada en la familia. Un grupo de supervisores expertos calificó la fidelidad de los profesionales clínicos al manual de la terapia centrada en la familia basándose en sesiones familiares grabadas. No detectamos diferencias en los puntajes de fidelidad entre los profesionales clínicos de las dos condiciones de capacitación, ni los pacientes tratados por profesionales clínicos en las capacitaciones de alta intensidad ni en las de baja intensidad tuvieron diferencias en los síntomas de manía o depresión al final del tratamiento. Los niveles de conflicto entre los padres y los hijos mejoraron en ambas condiciones. Aunque están basados en un estudio piloto, los resultados sugieren que la capacitación de baja intensidad de los profesionales clínicos de la comunidad en la terapia centrada en la familia es viable y puede dar como resultado un logro rápido de referentes de fidelidad sin pérdida aparente de eficacia del tratamiento.

Word usage in spontaneous speech as a predictor of depressive symptoms among youth at high risk for mood disorders.

BACKGROUND: We examined whether digital phenotyping of spontaneous speech, such as the use of specific word categories during speech samples, was associated with depressive symptoms in youth who were at familial and clinical risk for mood disorders. METHODS: Participants (ages 13-19) had active mood symptoms, mood instability, and at least one parent with bipolar or major depressive disorder. During a randomized trial of family-focused therapy, participants were instructed to make weekly calls to a central voice server and leave speech samples in response to automated prompts. We coded youths' speech samples with the Linguistic Inquiry and Word Count system and used machine learning to identify the combination of speech features that were most closely associated with the course of depressive symptoms over 18 weeks. RESULTS: A total of 253 speech samples were collected from 44 adolescents (mean age = 15.8 years; SD = 1.6) over 18 weeks. Speech containing affective processes, social processes, drives toward risk or reward, nonfluencies, and time orientation words were correlated with depressive symptoms at concurrent time periods (ps < 0.01). Machine learning analyses revealed that affective processes, nonfluencies, drives and risk words combined to most strongly predict changes in depressive symptoms over 18 weeks of treatment. LIMITATIONS: Study results were limited by the small sample and the exclusion of paralinguistic or contextual variables in analyzing speech samples. CONCLUSIONS: In youth at high risk for mood disorders, knowledge of speech patterns may inform prognoses during outpatient psychosocial treatment.

HIV-1 escape from the CCR5 antagonist maraviroc associated with an altered and less-efficient mechanism of gp120-CCR5 engagement that attenuates macrophage tropism.

Maraviroc (MVC) inhibits the entry of human immunodeficiency virus type 1 (HIV-1) by binding to and modifying the conformation of the CCR5 extracellular loops (ECLs). Resistance to MVC results from alterations in the HIV-1 gp120 envelope glycoproteins (Env) enabling recognition of the drug-bound conformation of CCR5. To better understand the mechanisms underlying MVC resistance, we characterized the virus-cell interactions of gp120 from in vitro-generated MVC-resistant HIV-1 (MVC-Res Env), comparing them with those of gp120 from the sensitive parental virus (MVC-Sens Env). In the absence of the drug, MVC-Res Env maintains a highly efficient interaction with CCR5, similar to that of MVC-Sens Env, and displays a relatively modest increase in dependence on the CCR5 N terminus. However, in the presence of the drug, MVC-Res Env interacts much less efficiently with CCR5 and becomes critically dependent on the CCR5 N terminus and on positively charged elements of the drug-modified CCR5 ECL1 and ECL2 regions (His88 and His181, respectively). Structural analysis suggests that the Val323 resistance mutation in the gp120 V3 loop alters the secondary structure of the V3 loop and the buried surface area of the V3 loop-CCR5 N terminus interface. This altered mechanism of gp120-CCR5 engagement dramatically attenuates the entry of HIV-1 into monocyte-derived macrophages (MDM), cell-cell fusion activity in MDM, and viral replication capacity in MDM. In addition to confirming that HIV-1 escapes MVC by becoming heavily dependent on the CCR5 N terminus, our results reveal novel interactions with the drug-modified ECLs that are critical for the utilization of CCR5 by MVC-Res Env and provide additional insights into virus-cell interactions that modulate macrophage tropism.

Effects of family intervention on psychosocial functioning and mood symptoms of youth at high risk for bipolar disorder.

OBJECTIVES: Family-focused therapy (FFT) is associated with reduced rates of mood episodes among youth at high risk for bipolar disorder (BD). In a randomized trial of FFT compared to a psychoeducation-only treatment (enhanced care, EC), we sought to determine if changes in psychosocial functioning mediate mood improvements among high-risk youth. METHOD: 119 youths with active mood symptoms and a family history of BD were randomized to either 4 months of FFT or EC. Participants were rated on mood symptom severity and provided self-ratings of psychosocial functioning across domains of family, social-emotional, and school functioning. Repeated measures mixed modeling and bootstrapped mediational analyses evaluated the effects of treatment conditions and psychosocial functioning on mood improvements immediately posttreatment and over 2 years of follow-up. RESULTS: Youths in FFT reported greater improvements in family functioning over 24 months compared to those in EC, F(5, 76.8) = 3.1, p < .05. Improvements in family functioning partially mediated participants' improvements in depressive symptoms, B = -0.22, p < .01; 95% CI [-0.55, -0.02]. The effects of FFT versus EC on family functioning were stronger among youth with comorbid anxiety and externalizing disorders than among youth without these comorbid disorders. CONCLUSIONS: The findings suggest a temporal link between changes in youths' perceptions of family functioning and improvements in depressive symptoms among high-risk youth in FFT. Family conflict and cohesion are important treatment targets for youth who present with early signs of BD. Future studies should examine whether changes in observational measures of family interaction precede improvements in mood among high-risk youth. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Using machine learning analyses of speech to classify levels of expressed emotion in parents of youth with mood disorders.

Expressed emotion (EE), a measure of attitudes among caregivers towards a patient with a psychiatric disorder, is a robust predictor of relapse across mood and psychotic disorders. Because the measurement of EE is time-intensive and costly, its use in clinical settings has been limited. In an effort to automate EE classification, we evaluated whether machine learning (ML) applied to lexical features of speech samples can accurately categorize parents as high or low in EE and in its subtypes (criticism, overinvolvement, and warmth). The sample was 123 parents of youth who had active mood symptoms and a family history of bipolar disorder. Using ML algorithms, we achieved 75.2-81.8% accuracy (sensitivities of ~0.7 and specificities of ~0.8) in classifying parents as high or low in EE and EE subtypes. Additionally, machine-derived EE classifications and observer-rated EE classifications had simiar relationships with youth mood symptoms, parental distress, and family conflict. Of note, criticism related to greater manic severity, parental distress, and family conflict. Study findings indicate that EE classification can be automated through lexical analysis and suggest potential for facilitating larger-scale applications in clinical settings. The results also provide initial indications of the digital phenotypes that underlie EE and its subtypes.

Development and Open Trial of a Technology-Enhanced Family Intervention for Adolescents at Risk for Mood Disorders.

AIM: Integrating psychosocial interventions with mobile apps may increase treatment engagement among adolescents. We examined the user experience, uptake, and clinical effects of a mobile-enhanced family-focused therapy (FFT) among adolescents at risk for mood disorders. METHOD: We created a mobile app containing 12 lesson plans corresponding to content of weekly FFT sessions, with modules concerning mood management, family communication and problem-solving. We pilot tested the app in an open trial of FFT (12 sessions in 18 weeks) for adolescents who had active depressive or hypomanic symptoms, a parent with mood disorder, and at least one parent who expressed high levels of criticism. Teens and parents made daily and weekly ratings of youths' moods, amount of parent/offspring criticism, and practice of FFT psychoeducational, communication or problem-solving skills. Independent evaluators interviewed adolescents at baseline and every 9 weeks over 27 weeks to measure symptom trajectories. RESULTS: Participants were adolescents (n=22; mean age 15.4 ± 1.8 years; 45.5% female) and their 34 parents. Completion of requested app assessment and skill practices averaged 46%-65% among adolescents and parents over 18 weeks of treatment. Adolescents showed significant improvement in clinician-rated depression scores over 27 weeks (Cohen's d=1.58, 95% CI, 0.83 to 2.32) and reported reductions in the amount of perceived criticism expressed by parents. LIMITATIONS: The uncontrolled design limits inferences about whether the mobile app augmented the effects of FFT on moods or family relationships. CONCLUSIONS: Mobile applications may enhance users' responses to family therapy and provide clinicians with information regarding clinical status. Clinicaltrials.gov NCT03913013.

A quantitative affinity-profiling system that reveals distinct CD4/CCR5 usage patterns among human immunodeficiency virus type 1 and simian immunodeficiency virus strains.

The affinity of human immunodeficiency virus (HIV) envelope for CD4 and CCR5 appears to be associated with aspects of R5 virus (virus using the CCR5 coreceptor) pathogenicity. However, entry efficiency results from complex interactions between the viral envelope glycoprotein and both CD4 and CCR5, which limits attempts to correlate viral pathogenicity with surrogate measures of envelope CD4 and CCR5 affinities. Here, we present a system that provides a quantitative and comprehensive characterization of viral entry efficiency as a direct interdependent function of both CD4 and CCR5 levels. This receptor affinity profiling system also revealed heretofore unappreciated complexities underlying CD4/CCR5 usage. We first developed a dually inducible cell line in which CD4 and CCR5 could be simultaneously and independently regulated within a physiologic range of surface expression. Infection by multiple HIV type 1 (HIV-1) and simian immunodeficiency virus isolates could be examined simultaneously for up to 48 different combinations of CD4/CCR5 expression levels, resulting in a distinct usage pattern for each virus. Thus, each virus generated a unique three-dimensional surface plot in which viral infectivity varied as a function of both CD4 and CCR5 expression. From this functional form, we obtained a sensitivity vector along with corresponding metrics that quantified an isolate's overall efficiency of CD4/CCR5 usage. When applied to viral isolates with well-characterized sensitivities to entry/fusion inhibitors, the vector metrics were able to encapsulate their known biological phenotypes. The application of the vector metrics also indicated that envelopes derived from elite suppressors had overall-reduced entry efficiencies compared to those of envelopes derived from chronically infected viremic progressors. Our affinity-profiling system may help to refine studies of R5 virus tropism and pathogenesis.

A mathematical model of intercellular signaling during epithelial wound healing.

Recent experiments monitoring the healing process of wounded epithelial monolayers have demonstrated the necessity of MAPK activation for coordinated cell movement after damage. This MAPK activity is characterized by two wave-like phenomena. One MAPK "wave" that originates immediately after injury, propagates deep into the cell sheet, away from the edge, and then rebounds back to the wound interface. After this initial MAPK activity has largely disappeared, a second MAPK front propagates slowly from the wound interface and also continues into the cell sheet, maintaining a sustained level of MAPK activity throughout the cell sheet. It has been suggested that the first wave is initiated by Reactive Oxygen Species (ROS) generated at the time of injury. In this work, we develop a minimal mathematical model that reproduces the observed behavior. The main ingredients of our model are a competition between ligand (e.g., Epithelial Growth Factor) and ROS for the activation of Epithelial Growth Factor Receptor, and a feedback loop between receptor occupancy and MAPK activation. We explore the mathematical properties of the model and look for traveling wave solutions consistent with the experimentally observed MAPK activity patterns.

Enhancement of cargo processivity by cooperating molecular motors.

Cellular cargo can be bound to cytoskeletal filaments by one or more active or passive molecular motors. Recent experiments have shown that the presence of auxiliary, nondriving motors results in an enhanced processivity of the cargo, compared to the case of a single active driving motor alone. We model the observed cooperative transport process using a stochastic model that describes the dynamics of two molecular motors, an active one that moves cargo unidirectionally along a filament track, and a passive one that acts as a tether. Analytical expressions obtained from our analysis are fit to experimental data to estimate the microscopic kinetic parameters of our model. Our analysis reveals two qualitatively distinct processivity-enhancing mechanisms: the passive tether can decrease the typical detachment rate of the active motor from the filament track or it can increase the corresponding reattachment rate. Comparing analytical results with experimental data, we can show unambiguously that in the case of kinesin transport on microtubules, a higher average run length arises mainly from the ability of the passive motor to keep the cargo close to the filament, enhancing the reattachment rate of recently detached active kinesin motors. On the other hand, in the case of myosin-driven transport along actin, the passive motor tightly tethers the cargo to the filament, suppressing the detachment rate of the active myosin.