Improving the Usefulness and Use of Meta-Analysis to Inform Policy and Practice.

This chapter begins with an overview of recent developments that have encouraged and facilitated greater use of research syntheses, including Meta-Analysis, to guide public policy and practice in education, workforce development, and social services. It discusses the role of Meta-Analysis for improving knowledge of the effectiveness of programs, policies, and practices and the applicability and generalizability of that knowledge to conditions other than those represented by the study samples and settings. The chapter concludes with recommendations for improving the potential of Meta-Analysis to accelerate knowledge development through changing how we design, conduct, and report findings of individual studies to maximize their usefulness in Meta-Analysis as well as how we produce and report Meta-Analysis findings. The paper includes references to resources supporting the recommendations.

Release of miR-29 Target Laminin C2 Improves Skin Repair.

miRNAs are small noncoding RNAs that regulate mRNA targets in a cell-specific manner. miR-29 is expressed in murine and human skin, where it may regulate functions in skin repair. Cutaneous wound healing model in miR-29a/b1 gene knockout mice was used to identify miR-29 targets in the wound matrix, where angiogenesis and maturation of provisional granulation tissue was enhanced in response to genetic deletion of miR-29. Consistently, antisense-mediated inhibition of miR-29 promoted angiogenesis in vitro by autocrine and paracrine mechanisms. These processes are likely mediated by miR-29 target mRNAs released upon removal of miR-29 to improve cell-matrix adhesion. One of these, laminin (Lam)-c2 (also known as laminin γ2), was strongly up-regulated during skin repair in the wound matrix of knockout mice. Unexpectedly, Lamc2 was deposited in the basal membrane of endothelial cells in blood vessels forming in the granulation tissue of knockout mice. New blood vessels showed punctate interactions between Lamc2 and integrin α6 (Itga6) along the length of the proto-vessels, suggesting that greater levels of Lamc2 may contribute to the adhesion of endothelial cells, thus assisting angiogenesis within the wound. These findings may be of translational relevance, as LAMC2 was deposited at the leading edge in human wounds, where it formed a basal membrane for endothelial cells and assisted neovascularization. These results suggest a link between LAMC2, improved angiogenesis, and re-epithelialization.

Plasma cell-derived mtDAMPs activate the macrophage STING pathway, promoting myeloma progression.

Mitochondrial damage-associated molecular patterns (mtDAMPs) include proteins, lipids, metabolites, and DNA and have various context-specific immunoregulatory functions. Cell-free mitochondrial DNA (mtDNA) is recognized via pattern recognition receptors and is a potent activator of the innate immune system. Cell-free mtDNA is elevated in the circulation of trauma patients and patients with cancer; however, the functional consequences of elevated mtDNA are largely undefined. Multiple myeloma (MM) relies upon cellular interactions within the bone marrow (BM) microenvironment for survival and progression. Here, using in vivo models, we describe the role of MM cell-derived mtDAMPs in the protumoral BM microenvironment and the mechanism and functional consequence of mtDAMPs in myeloma disease progression. Initially, we identified elevated levels of mtDNA in the peripheral blood serum of patients with MM compared with those of healthy controls. Using the MM1S cells engrafted into nonobese diabetic severe combined immunodeficient gamma mice, we established that elevated mtDNA was derived from MM cells. We further show that BM macrophages sense and respond to mtDAMPs through the stimulator of interferon genes (STING) pathway, and inhibition of this pathway reduces MM tumor burden in the KaLwRij-5TGM1 mouse model. Moreover, we found that MM-derived mtDAMPs induced upregulation of chemokine signatures in BM macrophages, and inhibition of this signature resulted in egress of MM cells from the BM. Here, we demonstrate that malignant plasma cells release mtDNA, a form of mtDAMPs, into the myeloma BM microenvironment, which in turn activates macrophages via STING signaling. We establish the functional role of these mtDAMP-activated macrophages in promoting disease progression and retaining MM cells in the protumoral BM microenvironment.

Acute Myeloid Leukaemia Drives Metabolic Changes in the Bone Marrow Niche.

Acute myeloid leukaemia (AML) is a highly proliferative cancer characterised by infiltration of immature haematopoietic cells in the bone marrow (BM). AML predominantly affects older people and outcomes, particularly in this difficult to treat population remain poor, in part due to inadequate response to therapy, and treatment toxicity. Normal haematopoiesis is supported by numerous support cells within the BM microenvironment or niche, including adipocytes, stromal cells and endothelial cells. In steady state haematopoiesis, haematopoietic stem cells (HSCs) primarily acquire ATP through glycolysis. However, during stress-responses HSCs rapidly transition to oxidative phosphorylation, enabled by mitochondrial plasticity. Historically it was thought that cancer cells preferentially used glycolysis for ATP production, however recently it has become evident that many cancers, including AML primarily use the TCA cycle and oxidative phosphorylation for rapid proliferation. AML cells hijack the stress-response pathways of their non-malignant counterparts, utilising mitochondrial changes to drive expansion. In addition, amino acids are also utilised by leukaemic stem cells to aid their metabolic output. Together, these processes allow AML cells to maximise their ATP production, using multiple metabolites and fuelling rapid cell turnover which is a hallmark of the disease. This review of AML derived changes in the BM niche, which enable enhanced metabolism, will consider the important pathways and discuss future challenges with a view to understanding how AML cells are able to hijack metabolic pathways and how we may elucidate new targets for potential therapies.

Using Iterative Experimentation to Accelerate Program Improvement: A Case Example.

BACKGROUND: This article offers a case example of how experimental evaluation methods can be coupled with principles of design-based implementation research (DBIR), improvement science (IS), and rapid-cycle evaluation (RCE) methods to provide relatively quick, low-cost, credible assessments of strategies designed to improve programs, policies, or practices. OBJECTIVES: This article demonstrates the feasibility and benefits of blending DBIR, IS, and RCE practices with embedded randomized controlled trials (RCTs) to improve the pace and efficiency of program improvement. RESEARCH DESIGN: This article describes a two-cycle experimental test of staff-designed strategies for improving a workforce development program. Youth enrolled in Year Up's Professional Training Corps (PTC) programs were randomly assigned to "improvement strategies" designed to boost academic success and persistence through the 6-month learning and development (L&D) phase of the program, when participants spend most of their program-related time in courses offered by partner colleges. SUBJECTS: The study sample includes 317 youth from three PTC program sites. MEASURES: The primary outcome measures are completion of the program's L&D phase and continued college enrollment beyond the L&D phase. RESULTS: The improvement strategies designed and tested during the study increased program retention through L&D by nearly 10 percentage points and increased college persistence following L&D by 13 percentage points. CONCLUSION: Blending DBIR, IS, and RCE principles with a multi-cycle RCT generated highly credible estimates of the efficacy of the tested improvement strategies within a relatively short period of time (18 months) at modest cost and with reportedly low burden for program staff.

Study Registration for the Field of Prevention Science: Considering Options and Paths Forward.

The practice of prospectively registering the details of intervention studies in a public database or registry is gaining momentum across disciplines as a strategy for increasing the transparency, credibility, and accessibility of study findings. In this article, we consider five registries that may be relevant for registration of intervention studies in the field of prevention science: ClinicalTrials.gov, the American Economic Association Registry of Randomized Controlled Trials (AEA RCT Registry), the Open Science Framework Preregistration (OSF Preregistration), the Registry for International Development Impact Evaluations (RIDIE), and the Registry of Efficacy and Effectiveness Studies (REES). We examine the five registries in terms of substantive focus, study designs, and contents of registry entries. We consider two paths forward for prospective registration of intervention studies in the field of prevention science: Path A: register all studies in ClinicalTrials.gov and Path B: allow individual researchers to select the registry with the "best fit." Lastly, we consider how the field might begin to establish norms around registration.

Decreasing nonmarital births and strengthening marriage to reduce poverty.

Since the 1970s, the share of U.S. children growing up in single-parent families has doubled, a trend that has disproportionately affected disadvantaged families. Paul Amato and Rebecca Maynard argue that reversing that trend would reduce poverty in the short-term and, perhaps more important, improve children's growth and development over the long term, thus reducing the likelihood that they would be poor when they grew up. The authors propose school and community programs to help prevent nonmarital births. They also propose to lower divorce rates by offering more educational programs to couples before and during marriage. Amato and Maynard recommend that all school systems offer health and sex education whose primary message is that parenthood is highly problematic for unmarried youth. They also recommend educating young people about methods to prevent unintended pregnancies. Ideally, the federal government would provide tested curriculum models that emphasize both abstinence and use of contraception. All youth should understand that unintended pregnancies are preventable and have enormous costs for the mother, the father, the child, and society. Strengthening marriage, argue the authors, is also potentially an effective strategy for fighting poverty. Researchers consistently find that premarital education improves marital quality and lowers the risk of divorce. About 40 percent of couples about to marry now participate in premarital education. Amato and Maynard recommend doubling that figure to 80 percent and making similar programs available for married couples. Increasing the number of couples receiving services could mean roughly 72,000 fewer divorces each year, or around 65,000 fewer children entering a single-parent family every year because of marital dissolution. After seven or eight years, half a million fewer children would have entered single-parent families through divorce. Efforts to decrease the share of children in single-parent households, say the authors, would almost certainly be cost effective in the long run and could reduce child poverty by 20 to 29 percent.