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Abstract Primary sclerosing cholangitis (PSC) is an idiopathic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of intra- and extrahepatic bile ducts. Osteoporosis is a frequent comorbidity in PSC, and we could previously demonstrate that IL17-dependent activation of bone resorption is the predominant driver of bone loss in PSC. Since we additionally observed an unexpected heterogeneity of bone mineral density in our cohort of 238 PSC patients, the present study focused on a comparative analysis of affected individuals with diagnosed osteoporosis (PSCOPO, n = 10) or high bone mass (PSCHBM, n = 7). The two groups were not distinguishable by various baseline characteristics, including liver fibrosis or serum parameters for hepatic function. In contrast, quantification of serum bile acid concentrations identified significant increases in the PSCOPO group, including glycoursodeoxycholic acid (GUDCA), an exogenous bile acid administered to both patient groups. Although cell culture experiments did not support the hypothesis that an increase in circulating bile levels is a primary cause of PSC-associated osteoporosis, the remarkable differences of endogenous bile acids and GUDCA in the serum of PSCOPO patients strongly suggest a yet unknown impairment of biliary metabolism and/or hepatic bile acid clearance in this patient subgroup, which is independent of liver fibrosis.

Brown adipose tissue (BAT) has emerged as an appealing therapeutic target for cardio metabolic diseases. BAT is a heat-producing organ and upon activation substantially lowers hyperlipidemia. In response to cold exposure, not only the uptake of lipids into BAT is increased but also the Cyp7b1-mediated synthesis of bile acids (BA) from cholesterol in the liver is triggered. In addition to their role for intestinal lipid digestion, BA act as endocrine signals that can activate thermogenesis in BAT. When exposed to cold temperatures, Cyp7b1−/− mice have compromised BAT function along with reduced fecal bile acid levels. Here, we aim to evaluate the role of Cyp7b1 for BAT-dependent lipid clearance. Using metabolic studies with radioactive tracers, we show that in response to a cold stimulus, BAT-mediated clearance of fatty acids derived from triglyceride-rich lipoproteins (TRL), and their remnants are reduced in Cyp7b1−/− mice. The impaired lipid uptake can be explained by reduced BAT lipoprotein lipase (LPL) levels and compromised organ activity in Cyp7b1−/− mice, which may be linked to impaired insulin signaling. Overall, our findings reveal that alterations of systemic lipoprotein metabolism mediated by cold-activated BAT are dependent, at least in part, on CYP7Β1.

The physiologic activation of thermogenic brown and white adipose tissues (BAT/WAT) by cold exposure triggers heat production by adaptive thermogenesis, a process known to ameliorate hyperlipidemia and protect from atherosclerosis. Mechanistically, it has been shown that thermogenic activation increases lipoprotein lipase (LPL)-dependent hydrolysis of triglyceride-rich lipoproteins (TRL) and accelerates the generation of cholesterol-enriched remnants and high-density lipoprotein (HDL), which promotes cholesterol flux from the periphery to the liver. HDL is also subjected to hydrolysis by endothelial lipase (EL) (encoded by LIPG). Genome-wide association studies have identified various variants of EL that are associated with altered HDL cholesterol levels. However, a potential role of EL in BAT-mediated HDL metabolism has not been investigated so far. In the present study, we show that in mice, cold-stimulated activation of thermogenic adipocytes induced expression of Lipg in BAT and inguinal WAT but that loss of Lipg did not affect gene expression of thermogenic markers. Furthermore, in both wild type (WT) and Lipg-deficient mice, activation of thermogenesis resulted in a decline of HDL cholesterol levels. However, cold-induced remodeling of the HDL lipid composition was different between WT and Lipg-deficient mice. Notably, radioactive tracer studies with double-labeled HDL indicated that cold-induced hepatic HDL cholesterol clearance was lower in Lipg-deficient mice. Moreover, this reduced clearance was associated with impaired macrophage-to-feces cholesterol transport. Overall, these data indicate that EL is a determinant of HDL lipid composition, cholesterol flux, and HDL turnover in conditions of high thermogenic activity.

Ambient temperature is an important determinant of both the alternative bile acid synthesis pathway controlled by oxysterol 7-α hydroxylase (CYP7B1) and the progression of metabolic-associated fatty liver disease (MAFLD). Here, we investigated whether CYP7B1 is involved in the etiology of MAFLD under conditions of low and high energy expenditure. For this, Cyp7b1−/− and wild type (WT) mice were fed a choline-deficient high-fat diet and housed either at 30 °C (thermoneutrality) or at 22 °C (mild cold). To study disease phenotype and underlying mechanisms, plasma and organ samples were analyzed to determine metabolic parameters, immune cell infiltration by immunohistology and flow cytometry, lipid species including hydroxycholesterols, bile acids and structural lipids. In WT and Cyp7b1−/− mice, thermoneutral housing promoted MAFLD, an effect that was more pronounced in CYP7B1-deficient mice. In these mice, we found higher plasma alanine aminotransferase activity, hyperlipidemia, hepatic accumulation of potentially harmful lipid species, aggravated liver fibrosis, increased inflammation and immune cell infiltration. Bile acids and hydroxycholesterols did not correlate with aggravated MAFLD in Cyp7b1−/− mice housed at thermoneutrality. Notably, an up-regulation of lipoprotein receptors was detected at 22 °C but not at 30 °C in livers of Cyp7b1−/− mice, suggesting that accelerated metabolism of lipoproteins carrying lipotoxic molecules counteracts MAFLD progression.

Activation of brown adipose tissue (BAT) reduces the development of atherosclerosis in animal models. Here the authors show that BAT activation also increases reverse cholesterol transport and turnover of high-density lipoprotein, which likely contributes to the anti-atherosclerotic effect of BAT activation.

The here described method can be used to estimate the uptake of orally provided cholesterol in mice. Briefly, mice are gavaged with radiolabeled cholesterol and 4 h later, organ distribution of the radiolabel is determined by liquid scintillation counting. The method has been applied successfully to determine dietary cholesterol handling of mice housed at different ambient temperatures

This article reports on a longitudinal project that attempts to situate student writing in the space between the worlds of academia and workplace. The project was conducted by several groups of students who took the same course in different years. The authors argue that student engagement in knowledge sharing with a workplace discourse community allows students to experi-ence the workplace context from within, adapt their academic knowledge to it, and apply this knowledge appropriately. Such longitudinal projects pro-vide students with an opportunity to enter into a productive dialogue with previous generations of students and build upon their work. Projects designed to ensure knowledge sharing and collaboration promise to help students bet-ter understand the intricacies of workplace communication and find connec-tions between academic knowledge and workplace practice.

Introduction A mental health provider's perception of how well an intervention can be carried out in their context (i.e., feasibility) is an important implementation outcome. This article aims to identify determinants of feasibility of trauma-focused cognitive behavioral therapy (TF-CBT) through a case-based causal approach. Method Data come from an implementation-effectiveness study in which lay counselors (teachers and community health volunteers) implemented a culturally adapted manualized mental health intervention, TF-CBT, delivered to teens who were previously orphaned and were experiencing posttraumatic stress symptoms and prolonged grief in Western Kenya. The intervention team identified combinations of determinants that led to feasibility among teacher- and community health volunteer-counselors through coincidence analysis. Results Among teacher-counselors, organizational-level factors (implementation climate, implementation leadership) determined moderate and high levels of feasibility. Among community health volunteer-counselors, a strong relationship between a clinical supervisor and the supervisee was the most influential determinant of feasibility. Conclusion Methodology and findings from this article can guide the assessment of determinants of feasibility and the development of implementation strategies for manualized mental health interventions in contexts like Western Kenya. Plain Language Summary A mental health provider's perception of how easy a therapy is to use in their work setting (i.e., feasibility) can impact whether the provider uses the therapy in their setting. Implementation researchers have recommended finding practices and constructs that lead to important indicators that a therapy will be used. However, limited research to our knowledge has searched and found practices and constructs that might determine feasibility of a therapy. This article uses existing data from a large trial looking at the continued use of a trauma-focused therapy to find practices and constructs that lead to moderate and high levels of feasibility. We found that in settings with a strong organizational structure that organization and leadership support for the therapy led to teachers in Kenya to perceive the therapy as easy to use. On the other hand, in settings with a weaker organizational structure, outside support from a clinical supervisor led to community health volunteers in Kenya perceiving the therapy as easy to use. The findings from this article can guide context-specific recommendations for increasing perceived therapy feasibility at the provider-, organization-, and policy levels.

Background Interdisciplinary collaboration and stakeholder engagement are key ingredients in implementation science research. However, effective and efficient collaboration can be limited by the complexity of implementation science terms. In this article, we argue that the development and use of plain language implementation science terms is an essential step to facilitate collaboration and engagement. Method We present an example of plain language development to portray the process and the potential benefits plain language can have on implementation science research. Implementation scientists and intervention experts codeveloped plain language implementation terms as a part of an implementation-effectiveness trial in western Kenya and in preparation for a stakeholder collaborative design meeting. Results The developed plain language terms facilitated wider stakeholder understanding and integration of implementation science findings that could inform the design of a stakeholder-led implementation coaching program. Conclusions We encourage the use of the plain language terms presented in this article, further translation, and additional development of other plain language terms for implementation science constructs.

Abstract Background There is a pervasive mental health treatment gap for children across the globe. Engaging stakeholders in child mental health evidence-based treatment (EBT) implementation projects may increase the likelihood of successful EBT implementation, thereby better addressing the treatment gap. However, little is known about the extent of stakeholder engagement to inform the implementation of child mental health EBTs. Methods We conducted a scoping review to characterize stakeholder engagement in child mental health EBT implementation projects, including what stakeholders are engaged, how they are engaged, when they are engaged, where they are engaged (i.e., location of projects), why they are engaged, and the reported impacts of stakeholder engagement. We searched seven databases: MEDLINE, PsycInfo, Embase, ERIC, CINAHL Complete, Scopus, and Web of Science Core Collection. To be included, studies had to report on some form of stakeholder engagement that was undertaken to inform or explain the implementation of a child mental health EBT. We performed data extraction and synthesis to describe key study and stakeholder characteristics, stakeholder engagement methods and rationales, reported impacts of stakeholder engagement, and quality of reporting on stakeholder engagement. Results In total, 122 manuscripts met our inclusion criteria, from which we identified a total of 103 unique child mental health EBT implementation projects. Projects spanned 22 countries, which included low-, lower-middle, upper-middle, and high-income countries. The largest number of projects was in the USA and conducted in public mental health settings. Most projects engaged EBT providers during the active implementation phase and with limited depth, often gathering information from stakeholders without sharing decision-making power in implementation efforts. Across projects, impacts of stakeholder engagement spanned all of Proctor and colleague’s implementation outcomes. Conclusions Given that stakeholder engagement is often shallow and with limited shared decision-making, additional effort should be made to increase engagement to preempt challenges to EBT implementation and ensure implementation success. Such efforts may ensure the just distribution of power in EBT implementation efforts. Trial registration All procedures were pre-registered on the Open Science Framework prior to conducting the literature search (DOI 10.17605/OSF.IO/GR9AP ).

BackgroundTask shifting is an effective model for increasing access to mental health treatment via lay counselors with less specialized training that deliver care under supervision. Mobile phones may present a low-technology opportunity to replace or decrease reliance on in-person supervision in task shifting, but important technical and contextual limitations must be examined and considered. ObjectiveGuided by human-centered design methods, we aimed to understand how mobile phones are currently used when supervising lay counselors, determine the acceptability and feasibility of mobile phone supervision, and generate solutions to improve mobile phone supervision. MethodsParticipants were recruited from a large hybrid effectiveness implementation study in western Kenya wherein teachers and community health volunteers were trained to provide trauma-focused cognitive behavioral therapy. Lay counselors (n=24) and supervisors (n=3) participated in semistructured interviews in the language of the participants’ choosing (ie, English or Kiswahili). Lay counselor participants were stratified by supervisor-rated frequency of mobile phone use such that interviews included high-frequency, average-frequency, and low-frequency phone users in equal parts. Supervisors rated lay counselors on frequency of phone contact (ie, calls and SMS text messages) relative to their peers. The interviews were transcribed, translated when needed, and analyzed using thematic analysis. ResultsParticipants described a range of mobile phone uses, including providing clinical updates, scheduling and coordinating supervision and clinical groups, and supporting research procedures. Participants liked how mobile phones decreased burden, facilitated access to clinical and personal support, and enabled greater independence of lay counselors. Participants disliked how mobile phones limited information transmission and relationship building between supervisors and lay counselors. Mobile phone supervision was facilitated by access to working smartphones, ease and convenience of mobile phone supervision, mobile phone literacy, and positive supervisor-counselor relationships. Limited resources, technical difficulties, communication challenges, and limitations on which activities can be effectively performed via mobile phone were barriers to mobile phone supervision. Lay counselors and supervisors generated 27 distinct solutions to increase the acceptability and feasibility of mobile phone supervision. Strategies ranged in terms of the resources required and included providing phones and airtime to support supervision, identifying quiet and private places to hold mobile phone supervision, and delineating processes for requesting in-person support. ConclusionsLay counselors and supervisors use mobile phones in a variety of ways; however, there are distinct challenges to their use that must be addressed to optimize acceptability, feasibility, and usability. Researchers should consider limitations to implementing digital health tools and design solutions alongside end users to optimize the use of these tools. International Registered Report Identifier (IRRID)RR2-10.1186/s43058-020-00102-9

Opportunities exist to leverage mobile phones to replace or supplement in-person supervision of lay counselors. However, contextual variables, such as network connectivity and provider preferences, must be considered. Using an iterative and mixed methods approach, we co-developed implementation guidelines to support the implementation of mobile phone supervision with lay counselors and supervisors delivering a culturally adapted trauma-focused cognitive behavioral therapy in Western Kenya. Guidelines were shared and discussed with lay counselors in educational outreach visits led by supervisors. We evaluated the impact of guidelines and outreach on the acceptability, feasibility, and usability of mobile phone supervision. Guidelines were associated with significant improvements in acceptability and usability of mobile phone supervision. There was no evidence of a significant difference in feasibility. Qualitative interviews with lay counselors and supervisors contextualized how guidelines impacted acceptability and feasibility – by setting expectations for mobile phone supervision, emphasizing importance, increasing comfort, and sharing strategies to improve mobile phone supervision. Introducing and discussing co-developed implementation guidelines significantly improved the acceptability and usability of mobile phone supervision. This approach may provide a flexible and scalable model to address challenges with implementing evidence-based practices and implementation strategies in lower-resourced areas.

Background: Physical health concerns (e.g. chronic pain, fatigue) are common among clients with posttraumatic stress disorder (PTSD). Prior research has indicated that clients report improved physical functioning and fewer physical health symptoms after receiving Cognitive Processing Therapy (CPT) for PTSD. However, less is known about the impact of physical functioning on the clients’ PTSD symptom improvement in CPT. Objective: The current study examined the patterns of change of and between physical functioning and PTSD symptoms over the course of CPT among a diverse military, veteran, and community sample. Method: We collected clients’ (N = 188) physical functioning and PTSD symptom severity prior to and during CPT using the 12-Item Short Form Health Survey and the PTSD Checklist. We used multilevel modelling to 1) evaluate the impact of baseline physical functioning on the PTSD symptom trajectory, 2) examine the trajectory of physical functioning, and 3) assess the dynamics between physical functioning and PTSD symptoms over the course of CPT. Results: Our multilevel analyses indicated that 1) physical functioning significantly improved for those with low levels of functioning prior to treatment, 2) poorer baseline physical functioning predicted slower improvements in PTSD symptoms, and 3) poorer physical functioning in one session predicted less PTSD symptom improvement by the next session. Conclusions: Our findings demonstrate that while physical functioning can interfere with PTSD symptom improvement, physical functioning can also improve over the course of CPT. In light of the interconnected nature of physical health and PTSD symptoms, clinicians may need to attend to lower levels of physical functioning when providing CPT or other trauma-focused therapies. Future research to determine whether specific treatment adaptations may benefit such clients is needed.

Abstract Background Identifying scalable strategies for assessing fidelity is a key challenge in implementation science. However, for psychosocial interventions, the existing, reliable ways to test treatment fidelity quality are often labor intensive, and less burdensome strategies may not reflect actual clinical practice. Cognitive behavioral therapies (CBTs) provide clinicians with a set of effective core elements to help treat a multitude of disorders, which, evidence suggests, need to be delivered with fidelity to maximize potential client impact. The current “gold standard” for rating CBTs is rating recordings of therapy sessions, which is extremely time-consuming and requires a substantial amount of initial training. Although CBTs can vary based on the target disorder, one common element employed in most CBTs is the use of worksheets to identify specific behaviors and thoughts that affect a client’s ability to recover. The present study will develop and evaluate an innovative new approach to rate CBT fidelity, by developing a universal CBT scoring system based on worksheets completed in therapy sessions. Methods To develop a scoring system for CBT worksheets, we will compile common CBT elements from a variety of CBT worksheets for a range of psychiatric disorders and create adherence and competence measures. We will collect archival worksheets from past studies to test the scoring system and assess test-retest reliability. To evaluate whether CBT worksheet scoring accurately reflects clinician fidelity, we will recruit clinicians who are engaged in a CBT for depression, anxiety, and/or posttraumatic stress disorder. Clinicians and clients will transmit routine therapy materials produced in session (e.g., worksheets, clinical notes, session recordings) to the study team after each session. We will compare observer-rated fidelity, clinical notes, and fidelity-rated worksheets to identify the most effective and efficient method to assess clinician fidelity. Clients will also be randomly assigned to either complete the CBT worksheets on paper forms or on a mobile application (app) to learn if worksheet format influences clinician and client experience or differs in terms of reflecting fidelity. Discussion Scoring fidelity using CBT worksheets may allow clinics to test fidelity in a short and effective manner, enhancing continuous quality improvement in the workplace. Clinicians and clinics can use such data to improve clinician fidelity in real time, leading to improved patient outcomes. Trial registration ClinicalTrials.gov NCT03479398. Retrospectively registered March 20, 2018.