Selective CAR-T cell mediated B cell depletion suppresses interferon signature in SLE.

Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single cell RNA sequencing and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell-mediated depletion of B cells in SLE patients. The resulting datasets do not only confirm a selective CAR T cell-mediated reset of the B cell response, but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type 1 interferon signaling. Our current data thus provide evidence for a causal relationship between the B cell response and the increased interferon signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and novel analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.

Navigating the field of implementation science towards maturity: challenges and opportunities.

BACKGROUND: The field of implementation science has significantly expanded in size and scope over the past two decades, although work related to understanding implementation processes have of course long preceded the more systematic efforts to improve integration of evidence-based interventions into practice settings. While this growth has had significant benefits to research, practice, and policy, there are some clear challenges that this period of adolescence has uncovered. MAIN BODY: This invited commentary reflects on the development of implementation science, its rapid growth, and milestones in its establishment as a viable component of the biomedical research enterprise. The authors reflect on progress in research and training, and then unpack some of the consequences of rapid growth, as the field has grappled with the competing challenges of legitimacy among the research community set against the necessary integration and engagement with practice and policy partners. The article then enumerates a set of principles for the field's next developmental stage and espouses the aspirational goal of a "big tent" to support the next generation of impactful science. CONCLUSION: For implementation science to expand its relevance and impact to practice and policy, researchers must not lose sight of the original purpose of the field-to support improvements in health and health care at scale, the importance of building a community of research and practice among key partners, and the balance of rigor, relevance, and societal benefit.

Shared decision-making in scaling and root planing.

INTRODUCTION: Estimate proportion of various approaches used by dental hygienists for engaging patients in decisions commonly arising during scaling and root planing. Distribution of approaches was compared across various task components in this procedure, practice experience of dental hygienists and patient compliance. MATERIALS AND METHODS: Survey of graduates from and students in a baccalaureate dental hygiene program. RESULTS: Paternalism (tell then do) and informed consent (give choices and reasons and ask for permission) were more common than shared decision-making (discuss alternatives, solicit patient input and arrive at a mutual decision) and disengagement (patient refusing offered service or avoiding further involvement) by a ratio of 4 to 1 for the first 2 compared with the latter 2. This relationship was held across selecting treatment, procedural adjuncts, homecare instructions and financial arrangements. Dental hygienists exhibited a range of personal preferences for engagement approaches. No-show rate, patient disengagement outside the office, was high (20%). CONCLUSION: Dental hygienists reported using 'more controlled' approaches to engaging patients in decisions regarding treatment. Patients may prefer to engage in more shared decisions and choose this approach by staying away from the office. This may underestimate patients' decisions to stay away from treatment, for example by not showing for completion of the treatment or disregarding homecare routines.

Epstein-Barr Virus-Associated Pulmonary Leiomyoma in a Patient With Untreated Human Immunodeficiency Virus Infection.

We report an Epstein-Barr virus-associated smooth muscle tumor in an adult male with AIDS. The patient had multiple lung nodules seen on computed tomography of the chest and an endobronchial lung tumor identified on bronchoscopy. Initiation of antiretroviral therapy slowed the progression of the tumors.

Embracing dynamic public health policy impacts in infectious diseases responses: leveraging implementation science to improve practice.

Rationale: The host-pathogen relationship is inherently dynamic and constantly evolving. Applying an implementation science lens to policy evaluation suggests that policy impacts are variable depending upon key implementation outcomes (feasibility, acceptability, appropriateness costs) and conditions and contexts. COVID-19 case study: Experiences with non-pharmaceutical interventions (NPIs) including masking, testing, and social distancing/business and school closures during the COVID-19 pandemic response highlight the importance of considering public health policy impacts through an implementation science lens of constantly evolving contexts, conditions, evidence, and public perceptions. As implementation outcomes (feasibility, acceptability) changed, the effectiveness of these interventions changed thereby altering public health policy impact. Sustainment of behavioral change may be a key factor determining the duration of effectiveness and ultimate impact of pandemic policy recommendations, particularly for interventions that require ongoing compliance at the level of the individual. Practical framework for assessing and evaluating pandemic policy: Updating public health policy recommendations as more data and alternative interventions become available is the evidence-based policy approach and grounded in principles of implementation science and dynamic sustainability. Achieving the ideal of real-time policy updates requires improvements in public health data collection and analysis infrastructure and a shift in public health messaging to incorporate uncertainty and the necessity of ongoing changes. In this review, the Dynamic Infectious Diseases Public Health Response Framework is presented as a model with a practical tool for iteratively incorporating implementation outcomes into public health policy design with the aim of sustaining benefits and identifying when policies are no longer functioning as intended and need to be adapted or de-implemented. Conclusions and implications: Real-time decision making requires sensitivity to conditions on the ground and adaptation of interventions at all levels. When asking about the public health effectiveness and impact of non-pharmaceutical interventions, the focus should be on when, how, and for how long they can achieve public health impact. In the future, rather than focusing on models of public health intervention effectiveness that assume static impacts, policy impacts should be considered as dynamic with ongoing re-evaluation as conditions change to meet the ongoing needs of the ultimate end-user of the intervention: the public.

Advancing the science of integrating multiple interventions by blending and bundling.

Cancer prevention and control research has produced a variety of effective interventions over the years, though most are single disease focused. To meet the Cancer Moonshot goal to reduce the cancer death rate by 50% by 2047, it may be necessary to overcome the limitations of siloed interventions that do not meet people's multiple needs and limitations in system capacity to deliver the increasing number of interventions in parallel. In this article, we propose integrating multiple evidence-based interventions as a potential solution. We define 2 types of integrated interventions, blended and bundled, and provide examples to illustrate each. We then offer a schematic and outline considerations for how to assemble blended or bundled interventions including looking at the intervention need or opportunity along the cancer continuum as well as co-occurring behaviors or motivations. We also discuss delivery workflow integration considerations including social-ecological level(s), context or setting, implementer, and intended beneficiary. Finally, in assembling integrated interventions, we encourage consideration of practice-based expertise and community and/or patient input. After assembly, we share thoughts related to implementation and evaluation of blended or bundled interventions. To conclude the article, we present multiple research opportunities in this space. With swift progress on these research directions, cancer prevention and control interventionists and implementation scientists can contribute to achieving the promise of the reignited Cancer Moonshot.

Efficacy of sustained knowledge translation (KT) interventions in chronic disease management in older adults: systematic review and meta-analysis of complex interventions.

BACKGROUND: Chronic disease management (CDM) through sustained knowledge translation (KT) interventions ensures long-term, high-quality care. We assessed implementation of KT interventions for supporting CDM and their efficacy when sustained in older adults. METHODS: Design: Systematic review with meta-analysis engaging 17 knowledge users using integrated KT. ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs) including adults (> 65 years old) with chronic disease(s), their caregivers, health and/or policy-decision makers receiving a KT intervention to carry out a CDM intervention for at least 12 months (versus other KT interventions or usual care). INFORMATION SOURCES: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from each database's inception to March 2020. OUTCOME MEASURES: Sustainability, fidelity, adherence of KT interventions for CDM practice, quality of life (QOL) and quality of care (QOC). Data extraction, risk of bias (ROB) assessment: We screened, abstracted and appraised articles (Effective Practice and Organisation of Care ROB tool) independently and in duplicate. DATA SYNTHESIS: We performed both random-effects and fixed-effect meta-analyses and estimated mean differences (MDs) for continuous and odds ratios (ORs) for dichotomous data. RESULTS: We included 158 RCTs (973,074 participants [961,745 patients, 5540 caregivers, 5789 providers]) and 39 companion reports comprising 329 KT interventions, involving patients (43.2%), healthcare providers (20.7%) or both (10.9%). We identified 16 studies described as assessing sustainability in 8.1% interventions, 67 studies as assessing adherence in 35.6% interventions and 20 studies as assessing fidelity in 8.7% of the interventions. Most meta-analyses suggested that KT interventions improved QOL, but imprecisely (36 item Short-Form mental [SF-36 mental]: MD 1.11, 95% confidence interval [CI] [- 1.25, 3.47], 14 RCTs, 5876 participants, I2 = 96%; European QOL-5 dimensions: MD 0.01, 95% CI [- 0.01, 0.02], 15 RCTs, 6628 participants, I2 = 25%; St George's Respiratory Questionnaire: MD - 2.12, 95% CI [- 3.72, - 0.51] 44 12 RCTs, 2893 participants, I2 = 44%). KT interventions improved QOC (OR 1.55, 95% CI [1.29, 1.85], 12 RCTS, 5271 participants, I2 = 21%). CONCLUSIONS: KT intervention sustainability was infrequently defined and assessed. Sustained KT interventions have the potential to improve QOL and QOC in older adults with CDM. However, their overall efficacy remains uncertain and it varies by effect modifiers, including intervention type, chronic disease number, comorbidities, and participant age. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084810.

Advancing adaptation of evidence-based interventions through implementation science: progress and opportunities.

While the recognition of the need to adapt interventions to improve their fit with populations and service systems has been well established within the scientific community, limited consideration of the role of adaptation within implementation science has impeded progress toward optimal uptake of evidence-based care. This article reflects on the traditional paths through which adapted interventions were studies, progress made in recent years toward better integration of the science of adaptation within implementation studies with reference to a special publication series, and next steps for the field to continue to build a robust knowledge base on adaptation.

Twenty years of collaborative research to enhance community practice for cancer prevention and control.

The Cancer Prevention and Control Research Network (CPCRN) was established in 2002 to conduct applied research and undertake related activities to translate evidence into practice, with a special focus on the unmet needs of populations at higher risk of getting cancer and dying from it. A network of academic, public health and community partners, CPCRN is a thematic research network of the Prevention Research Centers Program at the Centers for Disease Control and Prevention (CDC). The National Cancer Institute's Division of Cancer Control and Population Sciences (DCCPS) has been a consistent collaborator. The CPCRN has fostered research on geographically dispersed populations through cross-institution partnerships across the network. Since its inception, the CPCRN has applied rigorous scientific methods to fill knowledge gaps in the application and implementation of evidence-based interventions, and it has developed a generation of leading investigators in the dissemination and implementation of effective public health practices. This article reflects on how CPCRN addressed national priorities, contributed to CDC's programs, emphasized health equity and impacted science over the past twenty years and potential future directions.

Building a new regional home for implementation science: Annual Midwest Clinical & Translational Research Meetings.

The vision of the Central Society for Clinical and Translational Research (CSCTR) is to "promote a vibrant, supportive community of multidisciplinary, clinical, and translational medical research to benefit humanity." Together with the Midwestern Section of the American Federation for Medical Research, CSCTR hosts an Annual Midwest Clinical & Translational Research Meeting, a regional multispecialty meeting that provides the opportunity for trainees and early-stage investigators to present their research to leaders in their fields. There is an increasing national and global interest in implementation science (IS), the systematic study of activities (or strategies) to facilitate the successful uptake of evidence-based health interventions in clinical and community settings. Given the growing importance of this field and its relevance to the goals of the CSCTR, in 2022, the Midwest Clinical & Translational Research Meeting incorporated new initiatives and sessions in IS. In this report, we describe the role of IS in the translational research spectrum, provide a summary of sessions from the 2022 Midwest Clinical & Translational Research Meeting, and highlight initiatives to complement national efforts to build capacity for IS through the annual meetings.

Silencing miR-21-5p in sensory neurons reverses neuropathic allodynia via activation of TGF-ß-related pathway in macrophages.

Neuropathic pain remains poorly managed by current therapies, highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models, dorsal root ganglia (DRG) nociceptive neurons transfer miR-21 packaged in extracellular vesicles to macrophages that promote a proinflammatory phenotype and contribute to allodynia. Here we show that miR-21 conditional deletion in DRG neurons was coupled with lack of upregulation of chemokine CCL2 after nerve injury and reduced accumulation of CCR2-expressing macrophages, which showed TGF-ß-related pathway activation and acquired an M2-like antinociceptive phenotype. Indeed, neuropathic allodynia was attenuated after conditional knockout of miR-21 and restored by TGF-ßR inhibitor (SB431542) administration. Since TGF-ßR2 and TGF-ß1 are known miR-21 targets, we suggest that miR-21 transfer from injured neurons to macrophages maintains a proinflammatory phenotype via suppression of such an antiinflammatory pathway. These data support miR-21 inhibition as a possible approach to maintain polarization of DRG macrophages at an M2-like state and attenuate neuropathic pain.

Integrating pragmatic and implementation science randomized clinical trial approaches: a PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) analysis.

BACKGROUND: Over the past two decades, pragmatic and implementation science clinical trial research methods have advanced substantially. Pragmatic and implementation studies have natural areas of overlap, particularly relating to the goal of using clinical trial data to leverage health care system policy changes. Few investigations have addressed pragmatic and implementation science randomized trial methods development while also considering policy impact. METHODS: The investigation used the PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) and PRECIS-2-Provider Strategies (PRECIS-2-PS) tools to evaluate the design of two multisite randomized clinical trials that targeted patient-level effectiveness outcomes, provider-level practice changes and health care system policy. Seven raters received PRECIS-2 training and applied the tools in the coding of the two trials. Descriptive statistics were produced for both trials, and PRECIS-2 wheel diagrams were constructed. Interrater agreement was assessed with the Intraclass Correlation (ICC) and Kappa statistics. The Rapid Assessment Procedure Informed Clinical Ethnography (RAPICE) qualitative approach was applied to understanding integrative themes derived from the PRECIS-2 ratings and an end-of-study policy summit. RESULTS: The ICCs for the composite ratings across the patient and provider-focused PRECIS-2 domains ranged from 0.77 to 0.87, and the Kappa values ranged from 0.25 to 0.37, reflecting overall fair-to-good interrater agreement for both trials. All four PRECIS-2 wheels were rated more pragmatic than explanatory, with composite mean and median scores ≥ 4. Across trials, the primary intent-to-treat analysis domain was consistently rated most pragmatic (mean = 5.0, SD = 0), while the follow-up/data collection domain was rated most explanatory (mean range = 3.14-3.43, SD range = 0.49-0.69). RAPICE field notes identified themes related to potential PRECIS-2 training improvements, as well as policy themes related to using trial data to inform US trauma care system practice change; the policy themes were not captured by the PRECIS-2 ratings. CONCLUSIONS: The investigation documents that the PRECIS-2 and PRECIS-2-PS can be simultaneously used to feasibly and reliably characterize clinical trials with patient and provider-level targets. The integration of pragmatic and implementation science clinical trial research methods can be furthered by using common metrics such as the PRECIS-2 and PRECIS-2-PS. Future study could focus on clinical trial policy research methods development. TRIAL REGISTRATION: DO-SBIS ClinicalTrials.gov NCT00607620. registered on January 29, 2008. TSOS ClinicalTrials.gov NCT02655354, registered on July 27, 2015.

An evaluation of the role of miR-361-5p in senescence and systemic ageing.

Senescent cells are key regulators of ageing and age-associated disease. MicroRNAs (miRs) are a key component of the molecular machinery governing cellular senescence, with several known to regulate important genes associated with this process. We sought to identify miRs associated with both senescence and reversal by pinpointing those showing opposing directionality of effect in senescence and in response to senotherapy. Cellular senescence phenotypes were assessed in primary human endothelial cells following targeted manipulation of emergent miRNAs. Finally, the effect of conserved target gene knockdown on lifespan and healthspan was assessed in a C. elegans system in vivo. Three miRNAs (miR-5787, miR-3665 and miR-361-5p) demonstrated associations with both senescence and rejuvenation, but miR-361-5p alone demonstrated opposing effects in senescence and rescue. Treatment of late passage human endothelial cells with a miR-361-5p mimic caused a 14 % decrease in the senescent load of the culture. RNAi gene knockdown of conserved miR-361-5p target genes in a C. elegans model however resulted in adverse effects on healthspan and/or lifespan. Although miR-361-5p may attenuate aspects of the senescence phenotype in human primary endothelial cells, many of its validated target genes also play essential roles in the regulation or formation of the cytoskeletal network, or its interaction with the extracellular matrix. These processes are essential for cell survival and cell function. Targeting miR-361-5p alone may not represent a promising target for future senotherapy; more sophisticated approaches to attenuate its interaction with specific targets without roles in essential cell processes would be required.

Intervention delivery for embedded pragmatic clinical trials: Development of a tool to measure complexity.

BACKGROUND: Conducting an embedded pragmatic clinical trial in the workflow of a healthcare system is a complex endeavor. The complexity of the intervention delivery can have implications for study planning, ability to maintain fidelity to the intervention during the trial, and/or ability to detect meaningful differences in outcomes. METHODS: We conducted a literature review, developed a tool, and conducted two rounds of phone calls with NIH Pragmatic Trials Collaboratory Demonstration Project principal investigators to develop the Intervention Delivery Complexity Tool. After refining the tool, we piloted it with Collaboratory demonstration projects and developed an online version of the tool using the R Shiny application (https://duke-som.shinyapps.io/ICT-ePCT/). RESULTS: The 6-item tool consists of internal and external factors. Internal factors pertain to the intervention itself and include workflow, training, and the number of intervention components. External factors are related to intervention delivery at the system level including differences in healthcare systems, the dependency on setting for implementation, and the number of steps between the intervention and the outcome. CONCLUSION: The Intervention Delivery Complexity Tool was developed as a standard way to overcome communication challenges of intervention delivery within an embedded pragmatic trial. This version of the tool is most likely to be useful to the trial team and its health system partners during trial planning and conduct. We expect further evolution of the tool as more pragmatic trials are conducted and feedback is received on its performance outside of the NIH Pragmatic Trials Collaboratory.

Speeding implementation in cancer: The National Cancer Institute's Implementation Science Centers in Cancer Control.

The National Cancer Institute's Implementation Science Centers in Cancer Control (ISC3) Network represents a large-scale initiative to create an infrastructure to support and enable the efficient, effective, and equitable translation of approaches and evidence-based treatments to reduce cancer risk and improve outcomes. This Cancer MoonshotSM-funded ISC3 Network consists of 7 P50 Centers that support and advance the rapid development, testing, and refinement of innovative approaches to implement a range of evidence-based cancer control interventions. The Centers were designed to have research-practice partnerships at their core and to create the opportunity for a series of pilot studies that could explore new and sometimes risky ideas and embed in their infrastructure a 2-way engagement and collaboration essential to stimulating lasting change. ISC3 also seeks to enhance capacity of researchers, practitioners, and communities to apply implementation science approaches, methods, and measures. The Organizing Framework that guides the work of ISC3 highlights a collective set of 3 core areas of collaboration within and among Centers, including to 1) assess and incorporate dynamic, multilevel context; 2) develop and conduct rapid and responsive pilot and methods studies; and 3) build capacity for knowledge development and exchange. Core operating principles that undergird the Framework include open collaboration, consideration of the dynamic context, and engagement of multiple implementation partners to advance pragmatic methods and health equity and facilitate leadership and capacity building across implementation science and cancer control.

Dental hygiene students' participation as subjects in a randomized controlled trial: A full evidence-based dentistry experience.

PURPOSE: Demonstrate that dental hygiene students' participation in a randomized controlled trial comparing the plaque-removing capability of two toothbrushes provides a fuller understanding of the factors affecting the potential application of research to practice. METHODS: All students (N = 18) in a baccalaureate dental hygiene class were engaged in the design of a randomized controlled trial using the Consolidated Standards of Reporting Trials (CONSORT) standard and then participated as subjects in a staggered, repeated measures trial using plaque removal as the dependent variable and brush type, brush head wear, and time in study as independent variables. A debriefing of student participation and lessons learned from analyzing the results was conducted. RESULTS: The study found statistically significant differences in plaque removal capability. Brush type accounted for only 4% of the variance, while measures of brush head wear were inconsistent, and time in the study ("experimental fatigue") accounted for the most variance (9%). Students recognized and confirmed by their personal experiences that research that fails to focus on variance can create an overly optimistic impression of research effectiveness. There was strong agreement that subjects/patients vary widely and that performance depends on multiple factors. CONCLUSIONS: Dental hygiene students who participated as subjects in a randomized controlled trial comparing toothbrushes for plaque removal capacity felt that full analysis to account for all sources of variance and estimate the magnitude of measures of effect add to the value of reported research. Variation across patients is important in practice, if often overlooked as an "error" in the literature.

Toward an operational definition of shared decision making: A conceptual analysis.

RATIONALE: Shared decision making has been widely advocated and evaluated in diverse ways for 4 decades. AIMS AND OBJECTIVES: But there is scant evidence that it is commonly accepted by or has influence on practitioners' behaviour or that it positively affects patient health outcomes. This situation may be due in part to the absence of a commonly agreed operational definition of the construct. This is admitted in the literature and has led to multiple approaches to evaluation. METHOD: An operational definition is proposed based on ethical parity among parties, sharing of mutually interacting expectations and analysis of decisions as commitment to action rather than information. RESULTS: Shared decision making occurs when two autonomous and uncoerced agents both commit to actions that neither has reason to want to change based on their understanding of anticipated outcomes given the situation at hand and of the intended actions of the other party. CONCLUSION: It is a broader concept than providing information regarding treatment alternatives in the office.