Quasi-experimental study designs series –Paper 9: Collecting Data from Quasi-Experimental Studies

Objective: To identify variables that must be coded when synthesizing primary studies that use quasi-experimental designs.  Study Design and Setting: All quasi-experimental (QE) designs.  Results: When designing a systematic review of QE studies potential sources of heterogeneity – both theory-based and methodological – must be identified. We outline key components of inclusion criteria for syntheses of quasi-experimental studies. We provide recommendations for coding content-relevant and methodological variables, and outlined the distinction between bivariate effect sizes and partial (i.e., adjusted) effect sizes. Designs used and controls employed are viewed as of greatest importance. Potential sources of bias and confounding are also addressed.  Conclusion: Careful consideration must be given to inclusion criteria and the coding of theoretical and methodological variables during the design phase of a synthesis of quasi-experimental studies. The success of the meta-regression analysis relies on the data available to the meta-analyst. Omission of critical moderator variables (i.e., effect modifiers) will undermine the conclusions of a meta-analysis

Quasi-experimental study designs series – Paper 10: Synthesizing evidence for effects collected from quasi-experimental studies presents surmountable challenges

Objective: To outline issues of importance to analytic approaches to the synthesis of quasi-experiments (QEs), and to provide a statistical model for use in analysis. Study Design and Setting: We drew on the literatures of statistics, epidemiology, and social-science methodology to outline methods for synthesis of QE studies. The design and conduct of quasi-experiments, effect sizes from QEs, and moderator variables for the analysis of those effect sizes were discussed. Results: Biases, confounding, design complexities and comparisons across designs offer serious challenges to syntheses of QEs. Key components of meta-analyses of QEs were identified, including the aspects of QE study design to be coded and analyzed. Of utmost importance are the design and statistical controls implemented in the QEs. Such controls and any potential sources of bias and confounding must be modeled in analyses, along with aspects of the interventions and populations studied. Because of such controls, effect sizes from QEs are more complex than those from randomized experiments. A statistical meta-regression model that incorporates important features of the QEs under review was presented. Conclusion: Meta-analyses of quasi-experiments provide particular challenges, but thorough coding of intervention characteristics and study methods, along with careful analysis, should allow for sound inferences

A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation.

BACKGROUND: The mammalian DNA-damage response (DDR) has evolved to protect genome stability and maximize cell survival following DNA-damage. One of the key regulators of the DDR is p53, itself tightly regulated by MDM2. Following double-strand DNA breaks (DSBs), mediators including ATM are recruited to the site of DNA-damage. Subsequent phosphorylation of p53 by ATM and ATM-induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53-responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis. METHODS: In the current study, we investigated the stabilization and activation of p53 and associated DDR proteins in response to treatment of human colorectal cancer cells (HCT116p53+/+) with the MDM2 antagonist, Nutlin-3. RESULTS: Using immunoblotting, Nutlin-3 was observed to stabilize p53, and activate p53 target proteins. Unexpectedly, Nutlin-3 also mediated phosphorylation of p53 at key DNA-damage-specific serine residues (Ser15, 20 and 37). Furthermore, Nutlin-3 induced activation of CHK2 and ATM - proteins required for DNA-damage-dependent phosphorylation and activation of p53, and the phosphorylation of BRCA1 and H2AX - proteins known to be activated specifically in response to DNA damage. Indeed, using immunofluorescent labeling, Nutlin-3 was seen to induce formation of γH2AX foci, an early hallmark of the DDR. Moreover, Nutlin-3 induced phosphorylation of key DDR proteins, initiated cell cycle arrest and led to formation of γH2AX foci in cells lacking p53, whilst γH2AX foci were also noted in MDM2-deficient cells. CONCLUSION: To our knowledge, this is the first solid evidence showing a secondary role for Nutlin-3 as a DDR triggering agent, independent of p53 status, and unrelated to its role as an MDM2 antagonist

Intergenerational Community-Based Research and Creative Practice: Promoting Environmental Sustainability in Jinja, Uganda

This article critically reflects on the methodological approach developed for a recent project based in Jinja, Uganda, that sought to generate new forms of environmental knowledge and action utilizing diverse forms of creative intergenerational practice embedded within a broader framework of community-based participatory research. This approach provided new opportunities for intergenerational dialogue in Jinja, generated increased civic environmental engagement, and resulted in a participant-led campaign to share knowledge regarding sustainable biomass consumption. We term this approach intergenerational community-based research and creative practice. We discuss the advantages of this model while also reflecting throughout on the challenges of the approach

Early Intervention for Children Aged 0 to 2 Years With or at High Risk of Cerebral Palsy International Clinical Practice Guideline Based on Systematic Reviews:International Clinical Practice Guideline Based on Systematic Reviews

IMPORTANCE: Cerebral palsy (CP) is the most common childhood physical disability. Early intervention for children younger than 2 years with or at risk of CP is critical. Now that an evidence-based guideline for early accurate diagnosis of CP exists, there is a need to summarize effective, CP-specific early intervention and conduct new trials that harness plasticity to improve function and increase participation. Our recommendations apply primarily to children at high risk of CP or with a diagnosis of CP, aged 0 to 2 years. OBJECTIVE: To systematically review the best available evidence about CP-specific early interventions across 9 domains promoting motor function, cognitive skills, communication, eating and drinking, vision, sleep, managing muscle tone, musculoskeletal health, and parental support. EVIDENCE REVIEW: The literature was systematically searched for the best available evidence for intervention for children aged 0 to 2 years at high risk of or with CP. Databases included CINAHL, Cochrane, Embase, MEDLINE, PsycInfo, and Scopus. Systematic reviews and randomized clinical trials (RCTs) were appraised by A Measurement Tool to Assess Systematic Reviews (AMSTAR) or Cochrane Risk of Bias tools. Recommendations were formed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and reported according to the Appraisal of Guidelines, Research, and Evaluation (AGREE) II instrument. FINDINGS: Sixteen systematic reviews and 27 RCTs met inclusion criteria. Quality varied. Three best-practice principles were supported for the 9 domains: (1) immediate referral for intervention after a diagnosis of high risk of CP, (2) building parental capacity for attachment, and (3) parental goal-setting at the commencement of intervention. Twenty-eight recommendations (24 for and 4 against) specific to the 9 domains are supported with key evidence: motor function (4 recommendations), cognitive skills (2), communication (7), eating and drinking (2), vision (4), sleep (7), tone (1), musculoskeletal health (2), and parent support (5). CONCLUSIONS AND RELEVANCE: When a child meets the criteria of high risk of CP, intervention should start as soon as possible. Parents want an early diagnosis and treatment and support implementation as soon as possible. Early intervention builds on a critical developmental time for plasticity of developing systems. Referrals for intervention across the 9 domains should be specific as per recommendations in this guideline

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Massage Therapy for Osteoarthritis of the Knee: A Randomized Dose-Finding Trial

In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination.We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks.WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3-32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1-12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose.Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials.ClinicalTrials.gov NCT00970008

The Management of Disclosure in Children’s Accounts of Domestic Violence: Practices of Telling and Not Telling

Children and young people who experience domestic violence are often represented as passive witnesses, too vulnerable to tell the stories of their own lives. This article reports on findings from a 2 year European research project (Understanding Agency and Resistance Strategies, UNARS) with children and young people in Greece, Italy, Spain and the UK, who had experienced domestic violence. It explores children and young people’s understandings of their own capacity to reflect on and disclose their experiences Extracts from individual interviews with 107 children and young people (age 8–18) were analysed. Three themes are presented, that illustrate children and young people’s strategies for managing disclosure: (1) “Being silenced or choosing silence?”, explores children and young people’s practices of self-silencing; (2) “Managing disclosures: Finding ways to tell” outlines how children and young people value self-expression, and the strategies they use to disclose safely; and in (3) “Speaking with many voices” considers how children and young people’s accounts of their experiences are constituted relationally, and are often polyvocal. The article concludes that children and young people can be articulate, strategic and reflexive communicators, and that good support for families struggling with domestic violence must enable space for children and young people’s voice to be heard. This is possible only in an integrated framework able to encompass multiple layers and perspectives, rather than privileging the adult point of view. Practitioners who work with families affected by domestic violence need to recognize that children and young people are able to reflect on and speak about their experiences. This requires that attention is paid to the complexity of children and young people’s communication practices, and the relational context of those communications

Protective Efficacy of Serially Up-Ranked Subdominant CD8+ T Cell Epitopes against Virus Challenges

Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans

Increased Inter-Colony Fusion Rates Are Associated with Reduced COI Haplotype Diversity in an Invasive Colonial Ascidian Didemnum vexillum

Considerable progress in our understanding of the population genetic changes associated with biological invasions has been made over the past decade. Using selectively neutral loci, it has been established that reductions in genetic diversity, reflecting founder effects, have occurred during the establishment of some invasive populations. However, some colonial organisms may actually gain an ecological advantage from reduced genetic diversity because of the associated reduction in inter-colony conflict. Here we report population genetic analyses, along with colony fusion experiments, for a highly invasive colonial ascidian, Didemnum vexillum. Analyses based on mitochondrial cytochrome oxidase I (COI) partial coding sequences revealed two distinct D. vexillum clades. One COI clade appears to be restricted to the probable native region (i.e., north-west Pacific Ocean), while the other clade is present in widely dispersed temperate coastal waters around the world. This clade structure was supported by 18S ribosomal DNA (rDNA) sequence data, which revealed a one base-pair difference between the two clades. Recently established populations of D. vexillum in New Zealand displayed greatly reduced COI genetic diversity when compared with D. vexillum in Japan. In association with this reduction in genetic diversity was a significantly higher inter-colony fusion rate between randomly paired New Zealand D. vexillum colonies (80%, standard deviation ±18%) when compared with colonies found in Japan (27%, standard deviation ±15%). The results of this study add to growing evidence that for colonial organisms reductions in population level genetic diversity may alter colony interaction dynamics and enhance the invasive potential of newly colonizing species