Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.

How Do Treatment Protocols Affect the Use of Engagement Practices in Youth Mental Health Services?

PURPOSE: Treatment engagement poses challenges for youth mental health providers. With the expansion of evidence-based treatments (EBTs), providers face complex decisions regarding how to engage youth and families using available information sources. This study investigated how EBT protocols are associated with the selection and delivery of engagement practices. METHOD: Twenty engagement practices were coded in a sample of digital recordings of early treatment sessions (N = 193) from the Child STEPs in California study, a randomized trial testing modular treatment and community-implemented treatment for youth mental health problems. Data were collected on which protocols mental health providers reportedly used to guide their sessions and the protocols in which they had received training. We examined which information sources (i.e., the guiding protocol, other protocols in training history, unspecified source) were associated with observed engagement practices. RESULTS: In sessions guided by a protocol, most observed engagement practices were accounted for by the guiding protocol (p < .001), rather than protocols in training history or unspecified sources (p < .001). In sessions not guided by a protocol, most observed practices were accounted for by training history (p < .001). Practice frequency and extensiveness was generally greater when a protocol guided the session. CONCLUSIONS: Inclusion in protocols is associated with the selection and delivery of engagement practices, but this strategy might be insufficient for supporting the use of the full range of engagement practices supported by evidence. Supports are needed that leverage the engagement evidence base to ensure that selected practices empirically fit the engagement needs of youth and families.

The synaptosome-associated protein 23 (SNAP23) is necessary for proper myogenesis.

Vesicle-mediated transport is necessary for maintaining cellular homeostasis and proper signaling. The synaptosome-associated protein 23 (SNAP23) is a member of the SNARE protein family and mediates the vesicle docking and membrane fusion steps of secretion during exocytosis. Skeletal muscle has been established as a secretory organ; however, the role of SNAP23 in the context of skeletal muscle development is still unknown. Here, we show that depletion of SNAP23 in C2C12 mouse myoblasts reduces their ability to differentiate into myotubes as a result of premature cell cycle exit and early activation of the myogenic transcriptional program. This effect is rescued when cells are seeded at a high density or when cultured in conditioned medium from wild type cells. Proteomic analysis of collected medium indicates that SNAP23 depletion leads to a misregulation of exocytosis, including decreased secretion of the insulin-like growth factor 1 (IGF1), a critical protein for muscle growth, development, and function. We further demonstrate that treatment of SNAP23-depleted cells with exogenous IGF1 rescues their myogenic capacity. We propose that SNAP23 mediates the secretion of specific proteins, such as IGF1, that are important for achieving proper differentiation of skeletal muscle cells during myogenesis. This work highlights the underappreciated role of skeletal muscle as a secretory organ and contributes to the understanding of factors necessary for myogenesis.

A Novel Approach to the Assessment of Fidelity to a Cognitive Behavioral Therapy for PTSD Using Clinical Worksheets: A Proof of Concept With Cognitive Processing Therapy.

Fidelity monitoring is a critical indicator of psychotherapy quality and is central to successful implementation. A major barrier to fidelity in routine care is the lack of feasible, scalable, and valid measurement strategies. A reliable, low-burden fidelity assessment would promote sustained implementation of cognitive behavioral therapies (CBTs). The current study examined fidelity measurement for cognitive processing therapy (CPT) for posttraumatic stress disorder (PTSD) using clinical worksheets. External raters evaluated patient worksheets done as a part of treatment, both guided by the therapist and completed independently as homework. Results demonstrated that fidelity ratings from CPT session worksheets were feasible and efficient. Notably, they were strongly correlated with observer ratings of the fidelity of CPT strategies that were present on the worksheets. Agreement among ratings conducted by individuals with a range of experience with CPT was acceptable to high. There was not a main effect of therapist-guided, in-session worksheet ratings on PTSD symptom change. However, patient competence in completing worksheets independently was associated with greater PTSD symptom decline and in-session, therapist-guided worksheet completion was associated with larger symptom decreases among patients with high levels of competence. With further research and refinement, rating of worksheets may be an efficient way to examine therapist and patient skill in key CPT elements, and their interactions, compared to the gold standard of observer ratings of therapy video-recordings. Additional research is needed to determine if worksheets are an accurate and scalable alternative to gold standard observer ratings in settings in which time and resources are limited.

Bile acid composition regulates the manganese transporter Slc30a10 in intestine.

Bile acids (BAs) comprise heterogenous amphipathic cholesterol-derived molecules that carry out physicochemical and signaling functions. A major site of BA action is the terminal ileum, where enterocytes actively reuptake BAs and express high levels of BA-sensitive nuclear receptors. BA pool size and composition are affected by changes in metabolic health, and vice versa. One of several factors that differentiate BAs is the presence of a hydroxyl group on C12 of the steroid ring. 12α-Hydroxylated BAs (12HBAs) are altered in multiple disease settings, but the consequences of 12HBA abundance are incompletely understood. We employed mouse primary ileum organoids to investigate the transcriptional effects of varying 12HBA abundance in BA pools. We identified Slc30a10 as one of the top genes differentially induced by BA pools with varying 12HBA abundance. SLC30A10 is a manganese efflux transporter critical for whole-body manganese excretion. We found that BA pools, especially those low in 12HBAs, induce cellular manganese efflux and that Slc30a10 induction by BA pools is driven primarily by lithocholic acid signaling via the vitamin D receptor. Administration of lithocholic acid or a vitamin D receptor agonist resulted in increased Slc30a10 expression in mouse ileum epithelia. These data demonstrate a previously unknown role for BAs in intestinal control of manganese homeostasis.

Emergent Life Events: An In-Depth Investigation of Characteristics and Provider Responses during Youth Evidence-Based Treatment.

Emergent life events (ELEs), or acute client stressors disclosed within psychotherapy sessions, are not addressed by many evidence-based psychosocial treatments (EBTs). Preliminary provider-report studies suggest that ELEs may interfere with effective EBT implementation. The present study offers a detailed, observational examination of ELEs and their impact on EBT within therapy sessions. Data were observationally coded from 274 sessions with 55 primarily low-income, Latino youth clients (58% male, ages 5-15) in the modular EBT condition (Modular Approach to Therapy for Children [MATCH]) of the Child STEPs California trial. The ELE Coding System-Revised was used to measure ELEs, their characteristics, and provider responses to ELEs, including provider adherence to MATCH. Interrater reliability was generally high. At least one ELE was identified in 13% of randomly selected sessions. ELEs ranged widely in content, and their characteristics did not cluster together. Providers responded more frequently to ELEs with non-EBT content (e.g., information gathering, empathy) than EBT content; use of the ELE as a "teaching moment" for EBT content was the least common response (40% of ELEs). Multilevel regression analyses revealed that compared to sessions without an ELE, ELE sessions were significantly associated with reduced provider adherence to MATCH. Within ELE sessions, higher client distress when discussing the ELE was associated with reduced provider adherence to MATCH, but only when ELE severity was high. Beyond provider report, observational measures indicate that ELEs are prevalent and unpredictable in community settings and disrupt EBT delivery. Findings can inform the development of structured ELE management procedures to enhance existing EBTs.

Empirical Examinations of Modifications and Adaptations to Evidence-Based Psychotherapies: Methodologies, Impact, and Future Directions.

This review describes methods used to examine the modifications and adaptations to evidence-based psychological treatments (EBPTs), assesses what is known about the impact of modifications and adaptations to EBPTs, and makes recommendations for future research and clinical care. One hundred eight primary studies and three meta-analyses were identified. All studies examined planned adaptations, and many simultaneously investigated multiple types of adaptations. With the exception of studies on adding or removing specific EBPT elements, few studies compared adapted EBPTs to the original protocols. There was little evidence that adaptations in the studies were detrimental, but there was also limited consistent evidence that adapted protocols outperformed the original protocols, with the exception of adding components to EBPTs. Implications for EBPT delivery and future research are discussed.

Assessing Variability and Implementation Fidelity of Suicide Prevention Safety Planning in a Regional VA Healthcare System.

BACKGROUND: In 2008, the Veterans Health Administration (VHA) implemented the use of safety planning for suicide prevention. A safety plan is a list of strategies, developed collaboratively with a provider, for a patient to use when suicide risk is elevated. Despite the use of safety plans in VHA, little is known about implementation fidelity, the extent to which safety plans are delivered as intended, or patient-level outcomes of safety planning. AIMS: This study aimed to explore the implementation fidelity of safety planning in a regional VHA hospital and examine the associations between safety plan quality and completeness with patient outcomes. METHOD: A comprehensive chart review was conducted for patients who were flagged as high risk for suicide (N = 200). Completeness and quality were coded, as well as information about patient and provider interactions regarding safety plan use. RESULTS: Safety plans were mostly complete and of moderate quality, although variability existed, particularly in quality. Limited evidence of follow-up regarding safety planning was found in the medical charts. Higher quality was associated with fewer subsequent psychiatric hospitalizations. CONCLUSION: Variability in implementation fidelity and infrequent follow-up suggest a need for additional training and support regarding the use of safety plans for suicide prevention.

System-Level Influences on the Sustainability of a Cognitive Therapy Program in a Community Behavioral Health Network.

OBJECTIVE: The purpose of this study was to examine influences on the sustainability of a program to implement an evidence-based psychotherapy in a mental health system. METHODS: Interviews with program administrators, training consultants, agency administrators, and supervisors (N=24), along with summaries of program evaluation data and program documentation, were analyzed with a directed content-analytic approach. RESULTS: Findings suggested a number of interconnected and interacting influences on sustainability, including alignment with emerging sociopolitical influences and system and organizational priorities; program-level adaptation and evolution; intervention flexibility; strong communication, collaboration, planning, and support; and perceived benefit. These individual factors appeared to mutually influence one another and contribute to the degree of program sustainability achieved at the system level. Although most influences were positive, financial planning and support emerged as potentially both facilitator and barrier, and evaluation of benefits at the patient level remained a challenge. CONCLUSIONS: Several factors appeared to contribute to the sustainability of a psychosocial intervention in a large urban mental health system and warrant further investigation. Understanding interconnections between multiple individual facilitators and barriers appears critical to advancing understanding of sustainability in dynamic systems and adds to emerging recommendations for other implementation efforts. In particular, implications of the findings include the importance of implementation strategies, such as long-term planning, coalition building, clarifying roles and expectations, planned adaptation, evaluation, diversification of financing strategies, and incentivizing implementation.