Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells.

Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.

Modeling human heterogeneity of obesity with diversity outbred mice reveals a fat mass-dependent therapeutic window for resolvin E1.

Resolvin E1 (RvE1), a specialized pro-resolving mediator (SPM), improves glucose homeostasis in inbred mouse models of obesity. However, an impediment toward translation is that obesity is a highly heterogenous disease in which individuals will respond very differently to interventions such as RvE1. Thus, there is a need to study SPMs in the context of modeling the heterogeneity of obesity that is observed in humans. We investigated how RvE1 controls the concentration of key circulating metabolic biomarkers using diversity outbred (DO) mice, which mimic human heterogeneity. We first demonstrate that weights of DO mice can be classified into distinct distributions of fat mass (i.e., modeling differing classes of obesity) in response to a high-fat diet and in the human population when examining body composition. Next, we show RvE1 administration based on body weight for four consecutive days after giving mice a high-fat diet led to approximately half of the mice responding positively for serum total gastric inhibitory polypeptide (GIP), glucagon, insulin, glucose, leptin, and resistin. Interestingly, RvE1 improved hyperleptinemia most effectively in the lowest class of fat mass despite adjusting the dose of RvE1 with increasing adiposity. Furthermore, leptin levels after RvE1 treatment were the lowest in those mice that were also RvE1 positive responders for insulin and resistin. Collectively, these results suggest a therapeutic fat mass-dependent window for RvE1, which should be considered in future clinical trials. Moreover, the data underscore the importance of studying SPMs with heterogenous mice as a step toward precision SPM administration in humans.

Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.

Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention.

Enriched Marine Oil Supplement Increases Specific Plasma Specialized Pro-Resolving Mediators in Adults with Obesity.

BACKGROUND: Specialized pro-resolving mediators (SPMs), synthesized from PUFAs, resolve inflammation and return damaged tissue to homeostasis. Thus, increasing metabolites of the SPM biosynthetic pathway may have potential health benefits for select clinical populations, such as subjects with obesity who display dysregulation of SPM metabolism. However, the concentrations of SPMs and their metabolic intermediates in humans with obesity remains unclear. OBJECTIVES: The primary objective of this study was to determine if a marine oil supplement increased specific metabolites of the SPM biosynthetic pathway in adults with obesity. The second objective was to determine if the supplement changed the relative abundance of key immune cell populations. Finally, given the critical role of antibodies in inflammation, we determined if ex vivo CD19 + B-cell antibody production was modified by marine oil intervention. METHODS: Twenty-three subjects [median age: 56 y; BMI (in kg/m2): 33.1] consumed 2 g/d of a marine oil supplement for 28-30 d. The supplement was particularly enriched with 18-hydroxyeicosapentaenoic (HEPE), 14-hydroxydocosahexaenoic acid (14-HDHA), and 17-HDHA. Blood was collected pre- and postsupplementation for plasma mass spectrometry oxylipin and fatty acid analyses, flow cytometry, and B-cell isolation. Paired t-tests and Wilcoxon tests were used for statistical analyses. RESULTS: Relative to preintervention, the supplement increased 6 different HEPEs and HDHAs accompanied by changes in plasma PUFAs. Resolvin E1 and docosapentaenoic acid-derived maresin 1 concentrations were increased 3.5- and 4.7-fold upon intervention, respectively. The supplement did not increase the concentration of D-series resolvins and had no effect on the abundance of immune cells. Ex vivo B-cell IgG but not IgM concentrations were lowered postsupplementation. CONCLUSIONS: A marine oil supplement increased select SPMs and their metabolic intermediates in adults with obesity. Additional studies are needed to determine if increased concentrations of specific SPMs control the resolution of inflammation in humans with obesity. This trial was registered at clinicaltrials.gov as NCT04701138.

Lifespan Extension Via Dietary Restriction: Time to Reconsider the Evolutionary Mechanisms?

Dietary restriction (DR) is the most consistent environmental manipulation to extend lifespan. Originally thought to be caused by a reduction in caloric intake, recent evidence suggests that macronutrient intake underpins the effect of DR. The prevailing evolutionary explanations for the DR response are conceptualized under the caloric restriction paradigm, necessitating reconsideration of how or whether these evolutionary explanations fit this macronutrient perspective. In the authors' opinion, none of the current evolutionary explanations of DR adequately explain the intricacies of observed results; instead a context-dependent combination of these theories is suggested which is likely to reflect reality. In reviewing the field, it is proposed that the ability to track the destination of different macronutrients within the body will be key to establishing the relative roles of the competing theories. Understanding the evolution of the DR response and its ecological relevance is critical to understanding variation in DR responses and their relevance outside laboratory environments.

PACS downtime drill: testing departmental workflow with an enterprise imaging viewer and archive.

In today's workflow, radiologists rely on the picture archiving and communication system (PACS) to view images. Unplanned downtime causes significant delays in patient care and lengthy downtimes can have lasting effects on patient care and end-user confidence. The purpose of this manuscript is to describe the planning and implementation of a disaster drill where the departmental PACS was taken off-line and the hospital enterprise viewer was used for departmental image interpretation.

Creation of a Multi-vendor Image-Sharing Solution.

Transferring medical imaging studies from one institution to another is a common occurrence in today's medical practice. For the past two decades, radiology departments have relied on physical media (compact discs and digital video disks) and human couriers to accomplish image transfer. This mode of transfer is slow, prone to failure, and reliant on outdated technology. To address these shortcomings, multiple image-sharing vendors have created electronic, cloud-based solutions. While these solutions solve multiple problems, a new problem has been introduced: it is difficult to send or receive images across image-sharing platforms. In this work, we describe how we have developed a solution to share images across multiple vendor platforms.

Supporting the mental health needs of underserved communities: A qualitative study of barriers to accessing community resources.

This study examined the accessibility of community resources (e.g., welfare programs and afterschool programs) for underserved youth and families with mental health needs. Mental health professionals (n = 52) from a large community mental health and welfare agency serving predominantly low-income, Latinx families completed a semistructured interview that asked about the accessibility of community resources. Participant responses were coded using an inductive thematic analysis. Results showed that 71% of participants endorsed availability barriers (e.g., limited local programs), 37% endorsed logistical barriers (e.g., waitlists), 27% endorsed attitudinal barriers (e.g., stigmatized beliefs about help-seeking), and 23% endorsed knowledge barriers (e.g., lacking awareness about local programs). Professionals' perceived availability barriers were mostly consistent with the actual availability of community resources. Findings highlight the compounding challenges that underserved communities face and point to opportunities for promoting enhanced well-being and functioning for youth and families with mental health needs.

Disaster Planning During SARS-CoV-2/COVID: One Radiology Informatics Team's Story.

Disasters cause a major disruption to normal operations. Hospital information systems are often well-prepared for events such as fires or natural disasters. This type of disaster planning focuses on redundancy and manual workarounds. The SARS-CoV-2/COVID pandemic represented a new type of disaster for our radiology informatics team. In this pandemic, the information systems continued to work but the employees, and the computers that they worked with, had to be distanced. The purpose of this manuscript is to discuss the four phases of the disaster planning process: mitigation, planning, response, and recovery. We will illustrate the process with the example of how our radiology informatics team responded to the SARS-CoV-2/COVID pandemic.

Image-Enabling the Patient Portal of an Electronic Health Record.

Today, radiology departments still rely on compact disks to share imaging studies with patients. This practice is outdated as the majority of modern computers do not possess optical drives. In effect, hospitals are providing disks to patients to enable a single use, physical transport between two locations. This practice contrasts with the original goals of providing patients with their images: to empower ownership and provide transparency about their healthcare. The purpose of this manuscript is to implement an online platform for patient image viewing through an electronic health record patient portal. The number of study viewers was recorded daily over the first 90 days on our platform. During this time, the patients viewed 12,257 imaging studies. This represents 22% of the 56,413 imaging studies performed in our department. On average, there were 136 imaging studies viewed/day (range 52-250). We determined that an online platform enabling patients to view their images is feasible. At our hospital, a large percentage of patients quickly identified this feature and began using it to view their imaging studies.

Therapist-Observer Concordance in Ratings of EBP Strategy Delivery: Challenges and Targeted Directions in Pursuing Pragmatic Measurement in Children's Mental Health Services.

Pragmatic measures of therapist delivery of evidence-based practice (EBP) are critical to assessing the impact of large-scale, multiple EBP implementation efforts. As an initial step in the development of pragmatic measurement, the current study examined the concordance between therapist and observer ratings of items assessing delivery of EBP strategies considered essential for common child EBP targets. Possible EBP-, session-, and therapist-levels factors associated with concordance were also explored. Therapists and independent observers rated the extensiveness of therapist (n = 103) EBP strategy delivery in 680 community psychotherapy sessions in which six EBPs were used. Concordance between therapist- and observer-report of the extensiveness of therapist EBP strategy use was at least fair (ICC ≥ .40) for approximately half of the items. Greater therapist-observer concordance was observed in sessions where a structured EBP was delivered and in sessions where therapists reported being able to carry out planned activities. Findings highlighted conditions that may improve or hinder therapists' ability to report on their own EBP strategy delivery in a way that is consistent with independent observers. These results can help inform the development of pragmatic therapist-report measures of EBP strategy delivery and implementation efforts more broadly.

Using informatics to engage patients.

As a specialty, radiology has spent much of the last two decades implementing information systems that improve departmental efficiency and the ordering provider's access to information. While our patients have realized benefits such as improved access to care and reduced turnaround times, there has been little focus on using these information systems to improve patient engagement. In the last decade, society has shifted. Now, consumers in every industry expect to be able to use technology to help them accomplish different tasks from scheduling to communicating. Medicine, in general, has been slow to respond to the concept of the patient as a consumer. In this manuscript we describe some of the informatics efforts we have employed in our department to improve patient engagement. We present these initiatives, corresponding to each aspect of the radiology value stream, from the patient's point of view.

Community Mental Health Professionals' Perceptions About Engaging Underserved Populations.

This study explored mental health professionals' perceptions about barriers and facilitators to engaging underserved populations. Responses were coded using an iterative thematic analysis based on grounded theory. Results revealed that many professionals endorsed barriers to engaging ethnic minorities and families receiving social services. Client-provider racial and linguistic matching, therapy processes and procedures (e.g., nonjudgmental stance), and implementation supports (e.g., supervision) were commonly nominated as engagement facilitators. Many professionals felt that an organizational culture focused on productivity is detrimental to client engagement. Findings shed light on professionals' perceived barriers to delivering high-quality care to underserved communities and illuminate potential engagement strategies.

Choices in Treatment Integrity:Considering the Protocol and Consultant Recommendations in Child and Adolescent Therapy.

Codifying a complex treatment intervention into a manual necessarily involves simplifying procedures, possibly resulting in developer and expert adaptations that align with but are not fully consistent with the manualized content. This study evaluated the integrity of an evidence-based treatment to two information sources (i.e., an expert consultant and the treatment manual) within youth community mental health settings. Consultant recommendations were compared with manual-prescribed therapy procedures, which identified instances of agreement between the sources as well as consultant adaptations. To determine clinicians' integrity to each source, clinician-reported therapy procedures were compared with consultant recommendations and manual prescriptions. Participants consisted of 30 clinicians, five consultants, and 78 youths (53% male; M age = 9.73 years, SD = 2.84; 81% Latino). Findings indicated that consultants generally recommended content from the manual but also made frequent adaptations that involved changing the sequence or problem focus of practices and adding additional content. Clinicians followed both information sources in a majority of their sessions when these sources agreed but were more likely to follow only one or neither source when they disagreed. Findings suggest that consultants often make adaptations to the manual and that clinicians are more likely to employ recommendations from the manual and/or consultant when the information sources are in agreement. Although it is as yet unclear whether consultant recommendations are effective when they differ from the prescriptions of the manual, results from this study indicate that information sources that supplement treatment manuals may benefit clinical decision making.

Comparing Agency Leader and Therapist Perspectives on Evidence-Based Practices: Associations with Individual and Organizational Factors in a Mental Health System-Driven Implementation Effort.

Agency leaders and therapists are essential stakeholders in implementation of evidence-based practices (EBPs) within publicly-funded mental health services. Little is known about how these stakeholders differ in their perceptions of specific EBPs and which individual and organizational factors differentially influence these perceptions. Within the context of a system-driven implementation of multiple EBPs, survey data from 160 leaders and 720 therapists were examined to assess differences in perceptions of six EBPs. Findings indicated that leaders and therapists have unique perspectives and preferences regarding EBPs that are shaped by distinct sociodemographic and professional characteristics and aspects of organizational functioning.

Agency responses to a system-driven implementation of multiple evidence-based practices in children's mental health services.

BACKGROUND: Large mental health systems are increasingly using fiscal policies to encourage the implementation of multiple evidence-based practices (EBPs). Although many implementation strategies have been identified, little is known about the types and impacts of strategies that are used by organizations within implementation as usual. This study examined organizational-level responses to a fiscally-driven, rapid, and large scale EBP implementation in children's mental health within the Los Angeles County Department of Mental Health. METHODS: Qualitative methods using the principles of grounded theory were used to characterize the responses of 83 community-based agencies to the implementation effort using documentation from site visits conducted 2 years post reform. RESULTS: Findings indicated that agencies perceived the rapid system-driven implementation to have both positive and negative organizational impacts. Identified challenges were primarily related to system implementation requirements rather than to characteristics of specific EBPs. Agencies employed a variety of implementation strategies in response to the system-driven implementation, with agency size associated with implementation strategies used. Moderate- and large-sized agencies were more likely than small agencies to have employed systematic strategies at multiple levels (i.e., organization, therapist, client) to support implementation. CONCLUSIONS: These findings are among the first to characterize organizational variability in response to system-driven implementation and suggest ways that implementation interventions might be tailored by organizational characteristics.

How Intervention and Implementation Characteristics Relate to Community Therapists' Attitudes Toward Evidence-Based Practices: A Mixed Methods Study.

Therapists' perceptions toward evidence-based practices (EBPs) are important in implementation efforts, however little is known about characteristics of EBPs associated with more positive attitudes. This mixed-methods study examined how intervention and implementation characteristics of six EBPs related to therapist attitudes. Quantitative analysis of 793 cross-sectional surveys revealed that therapists endorsed more positive attitudes toward EBPs with (1) prescribed session content and order and (2) required consultation. Associations between these intervention and implementation characteristics and attitudes were not moderated by therapist experience or emotional exhaustion. Qualitative analyses complemented quantitative findings, indicating that "structure" was appealing for interventions and that therapists felt supported by consultation.

Measuring Sustainment of Multiple Practices Fiscally Mandated in Children's Mental Health Services.

Examining sustainment of multiple evidence-based practices is crucial to understanding the processes and outcomes of system-driven implementation efforts that are increasingly common. This study used administrative claims data to characterize volume and penetration of six practices over 19 fiscal quarters following initial implementation within the context of a system-driven, fiscally mandated implementation effort in Los Angeles County Department of Mental Health's Prevention and Early Intervention services. Patterns of volume changes over time revealed an overall ramp up of practice claims over time, but variability in patterns of volume and penetration for each practice. Findings varied by the methods used to index and analyze volume and penetration. Furthermore, a number of client case-mix and therapist characteristics were associated with the volume of therapists' claims for each practice relative to their claims for the other practices.

Steroid hormone signaling is essential to regulate innate immune cells and fight bacterial infection in Drosophila.

Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. Drosophila metamorphosis represents a striking example of drastic and systemic physiological changes that need to be integrated with the innate immune system. However, nothing is known about the mechanisms that coordinate development and immune cell activity in the transition from larva to adult. Here, we reveal that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. Although it is generally accepted that steroid hormones impact immunity in mammals, their action on monocytes (e.g. macrophages and neutrophils) is still not well understood. Here in a simpler model system, we used an approach that allows in vivo, cell autonomous analysis of hormonal regulation of innate immune cells, by combining genetic manipulation with flow cytometry, high-resolution time-lapse imaging and tissue-specific transcriptomic analysis. We show that in response to ecdysone, hemocytes rapidly upregulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic and local production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential for hemocyte immune functions and survival after infection. Microarray analysis of hemocytes revealed a large set of genes regulated at metamorphosis by EcR signaling, among which many are known to function in cell motility, cell shape or phagocytosis. This study demonstrates an important role for steroid hormone regulation of immunity in vivo in Drosophila, and paves the way for genetic dissection of the mechanisms at work behind steroid regulation of innate immune cells.

Integrity of evidence-based practice: are providers modifying practice content or practice sequencing?

This study examined patterns of evidence-based treatment (EBT) implementation within community settings by evaluating integrity along separate dimensions of practice content (PC; a session included the prescribed procedure) and practice sequencing (a session occurred in the prescribed sequence) within a recent randomized effectiveness trial. We measured whether sessions showed integrity to PC and to flexible or linear practice sequences. Findings revealed that providers tended to incorporate content from the EBT protocol in most treatment sessions, but that the sequencing of the sessions was often modified, suggesting that providers are amenable to evidence-based procedures, but not necessarily their prescribed arrangement.