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"Michele, P"
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Addressing Vaccine Hesitancy in BIPOC Communities — Toward Trustworthiness, Partnership, and Reciprocity
As Covid vaccines are rolled out, it’s time to shift the focus from a sole emphasis on changing hearts and minds among members of BIPOC communities to ensuring that institutions are trustworthy, transparent, and engaged with communities.
Journal Article
Health and wellness
\"This series is designed for public library patrons and high school students who are developing the skills needed to transition successfully in the real world - whether in the context of college, the workplace, or their personal lives. In a progressive series of volumes, the Life and Career Skills Series treats the following initial themes: Volume 3: Health and Wellness - Principles of good nutrition, exercise, mental health, medical insurance This volume covers 50 topics and contains overviews, but emphasizes scenarios to help public library patrons and students work through the real-life application of the principles covered. Each volume includes an extensive resource section listing organizations, support groups, websites, and more. Though designed as public library resource, this set is also useful in the high school classroom\"-- Provided by publisher.
Book
R-loops Associated with Triplet Repeat Expansions Promote Gene Silencing in Friedreich Ataxia and Fragile X Syndrome
Friedreich ataxia (FRDA) and Fragile X syndrome (FXS) are among 40 diseases associated with expansion of repeated sequences (TREDs). Although their molecular pathology is not well understood, formation of repressive chromatin and unusual DNA structures over repeat regions were proposed to play a role. Our study now shows that RNA/DNA hybrids (R-loops) form in patient cells on expanded repeats of endogenous FXN and FMR1 genes, associated with FRDA and FXS. These transcription-dependent R-loops are stable, co-localise with repressive H3K9me2 chromatin mark and impede RNA Polymerase II transcription in patient cells. We investigated the interplay between repressive chromatin marks and R-loops on the FXN gene. We show that decrease in repressive H3K9me2 chromatin mark has no effect on R-loop levels. Importantly, increasing R-loop levels by treatment with DNA topoisomerase inhibitor camptothecin leads to up-regulation of repressive chromatin marks, resulting in FXN transcriptional silencing. This provides a direct molecular link between R-loops and the pathology of TREDs, suggesting that R-loops act as an initial trigger to promote FXN and FMR1 silencing. Thus R-loops represent a common feature of nucleotide expansion disorders and provide a new target for therapeutic interventions.
Journal Article
Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers
To assess inter-rater reliability and validity of the Newcastle Ottawa Scale (NOS) used for methodological quality assessment of cohort studies included in systematic reviews.
Two reviewers independently applied the NOS to 131 cohort studies included in eight meta-analyses. Inter-rater reliability was calculated using kappa (κ) statistics. To assess validity, within each meta-analysis, we generated a ratio of pooled estimates for each quality domain. Using a random-effects model, the ratios of odds ratios for each meta-analysis were combined to give an overall estimate of differences in effect estimates.
Inter-rater reliability varied from substantial for length of follow-up (κ = 0.68, 95% confidence interval [CI] = 0.47, 0.89) to poor for selection of the nonexposed cohort and demonstration that the outcome was not present at the outset of the study (κ = −0.03, 95% CI = −0.06, 0.00; κ = −0.06, 95% CI = −0.20, 0.07). Reliability for overall score was fair (κ = 0.29, 95% CI = 0.10, 0.47). In general, reviewers found the tool difficult to use and the decision rules vague even with additional information provided as part of this study. We found no association between individual items or overall score and effect estimates.
Variable agreement and lack of evidence that the NOS can identify studies with biased results underscore the need for revisions and more detailed guidance for systematic reviewers using the NOS.
Journal Article
Increasing Black, Indigenous and People of Color participation in clinical trials through community engagement and recruitment goal establishment
Longstanding social and economic inequities elevate health risks and vulnerabilities for Black, Indigenous and People of Color (BIPOC) communities. Engagement of BIPOC communities in infectious disease research is a critical component in efforts to increase vaccine confidence, acceptability, and uptake of future approved products. Recent data highlight the relative absence of BIPOC communities in vaccine clinical trials. Intentional and effective community engagement methods are needed to improve BIPOC inclusion. We describe the methods utilized for the successful enrollment of BIPOC participants in the U.S. Government (USG)-funded COVID-19 Prevention Network (CoVPN)-sponsored vaccine efficacy trials and analyze the demographic and enrollment data across the efficacy trials to inform future efforts to ensure inclusive participation. Across the four USG-funded COVID-19 vaccine clinical trials for which data are available, 47% of participants enrolled at CoVPN sites in the US were BIPOC. White enrollment outpaced enrollment of BIPOC participants throughout the accrual period, requiring the implementation of strategies to increase diverse and inclusive enrollment. Trials opening later benefitted considerably from strengthened community engagement efforts, and greater and more diverse volunteer registry records. Despite robust fiscal resources and a longstanding collaborative and collective effort, enrollment of White persons outpaced that of BIPOC communities. With appropriate resources, commitment and community engagement expertise, the equitable enrollment of BIPOC individuals can be achieved. To ensure this goal, intentional efforts are needed, including an emphasis on diversity of enrollment in clinical trials, establishment of enrollment goals, ongoing robust community engagement, conducting population-specific trials, and research to inform best practices.
Journal Article
A Systematic Review of Social Media Use to Discuss and View Deliberate Self-Harm Acts
To conduct a systematic review of studies of social media platforms used by young people to discuss and view deliberate self-harm.
11 electronic databases were searched from January 2000 to January 2012 for primary research; in June 2014 an updated search of Medline was conducted. Grey literature sources were also searched. Search results were screened by two reviewers. Data were extracted by one reviewer and verified by another. Methodological quality was assessed using the Mixed Methods Appraisal Tool.
Due to heterogeneity in study objectives and outcomes, results were not pooled; a narrative analysis is presented. 26 studies were included. Most were conducted in Canada or the UK (30.8% each), used qualitative designs (42.3%), and evaluated discussion forums (73.1%). Participants were most often aged 19-21 years (69.2%), female (mean 68.6%), and 19.2% had a documented history of depression. The social media platforms evaluated were commonly supportive and provided a sense of community among users. Support included suggestions for formal treatment, advice on stopping self-harming behavior, and encouragement. Harms included normalizing and accepting self-harming behavior; discussion of motivation or triggers, concealment, suicidal ideation or plans; and live depictions of self-harm acts.
Although this evidence is limited by its descriptive nature, studies identify beneficial and detrimental effects for young people using social media to discuss and view deliberate self-harm. The connections users make online may be valuable to explore for therapeutic benefit. Prospective, longitudinal investigations are needed to identify short- and long-term potential harms associated with use.
Journal Article
Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial
In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.
Authors have previously reported on the efficacy and safety of the recombinant spike protein nanoparticle vaccine, NVX-CoV2373, in healthy adults. In this work, they assess anti-spike binding IgG, anti-RBD binding IgG and neutralising antibody titer as correlates of risk and protection against COVID-19.
Journal Article
Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion
Two papers in this issue, by Bruns
et al
. and Zhao
et al
., show that megakaryocytes constitute a niche for hematopoietic stem cells in the mouse bone marrow and produce factors that regulate hematopoietic stem cell quiescence and proliferation.
In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of blood cells while also preventing HSC exhaustion
1
. All putative niche cells suggested thus far have a nonhematopoietic origin
2
,
3
,
4
,
5
,
6
,
7
,
8
. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective
in vivo
depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast,
Cxcl4
−/−
mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.
Journal Article