Abstract WMP37: Methodological Quality and Meta-Analysis of Animal Studies of Mesenchymal Stromal Cells for Ischemic Stroke

INTRODUCTION: Mesenchymal stromal cells (MSC) are multipotent cells that support numerous restorative processes after stroke. The ease of isolation and immunoprivileged status of MSC have stimulated numerous preclinical stroke studies. We performed a meta-analysis to estimate study quality, size of behavioral effects, and the impact of variables such as timing of MSC administration in relation to stroke onset. METHODS: Studies of MSC and stroke were identified through PubMed and Web of Science. Studies of hemorrhage, not in English, or using modified MSC were excluded. A Quality Score was determined for each study, estimating methodological quality using 10 criteria derived from STAIR guidelines, with higher Quality Scores reflecting greater compliance with issues such as randomization and outcome blinding. Outcome data extracted for MSC and control arms were used to derive estimates of effect size using Cohen’s d. RESULTS: A total of 46 studies met criteria, with 39 studying rats, 6 mice, and 1 primates. There were 61 treatment groups, as some studies had >1 independent MSC treatment arms; MSC were introduced intravenously in 41, intracerebrally in 15, and intraarterially in 6. MSC source was rat in 24, human in 16, and mouse in 6. Time of MSC administration ranged from 5 weeks pre- to 1 month post-stroke. MSC dose ranged from 1x10^4 to 3.25x10^7. The median Quality Score was 6 (IQR 5-7). Quality Score was not related to time of MSC administration relative to stroke or to behavioral effect size. Median effect size was 2.05 for the Modified Neurological Severity Scale (n=23), 1.88 for Adhesive Removal Test (n=19), and 2.70 for the Rotarod Test (n=14). Effect sizes were substantial across all routes of administration and differed only for the mNSS (p<0.04), favoring the IC route. Effect size did not vary with time of MSC administration relative to stroke for any behavioral measure. CONCLUSIONS: The quality of preclinical MSC stroke studies has generally been good. MSC consistently provide very large behavioral benefits, across scales and routes of administration. The magnitude of behavioral effects was not related to the Quality Score or to the time of MSC administration relative to stroke. These findings support translation of MSC to human trials.

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Systematic review and meta-analysis of preclinical studies testing mesenchymal stromal cells for traumatic brain injury

npj Regenerative Medicine ◽

10.1038/s41536-021-00182-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Francesca Pischiutta ◽

Enrico Caruso ◽

Alessandra Lugo ◽

Helena Cavaleiro ◽

Nino Stocchetti ◽

...

Keyword(s):

Systematic Review ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Mesenchymal Stromal Cells ◽

Effect Size ◽

Stromal Cells ◽

Meta Analysis ◽

Similar Efficacy ◽

Post Injury ◽

Neurological Improvement

AbstractMesenchymal stromal cells (MSCs) are widely used in preclinical models of traumatic brain injury (TBI). Results are promising in terms of neurological improvement but are hampered by wide variability in treatment responses. We made a systematic review and meta-analysis: (1) to assess the quality of evidence for MSC treatment in TBI rodent models; (2) to determine the effect size of MSCs on sensorimotor function, cognitive function, and anatomical damage; (3) to identify MSC-related and protocol-related variables associated with greater efficacy; (4) to understand whether MSC manipulations boost therapeutic efficacy. The meta-analysis included 80 studies. After TBI, MSCs improved sensorimotor and cognitive deficits and reduced anatomical damage. Stratified meta-analysis on sensorimotor outcome showed similar efficacy for different MSC sources and for syngeneic or xenogenic transplants. Efficacy was greater when MSCs were delivered in the first-week post-injury, and when implanted directly into the lesion cavity. The greatest effect size was for cells embedded in matrices or for MSC-derivatives. MSC therapy is effective in preclinical TBI models, improving sensorimotor, cognitive, and anatomical outcomes, with large effect sizes. These findings support clinical studies in TBI.

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Mesenchymal stromal cells for COVID-19: A living systematic review protocol

10.1101/2020.04.13.20064162 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gabriel Rada ◽

Javiera Corbalán ◽

Patricio Rojas ◽

Keyword(s):

Systematic Review ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Direct Evidence ◽

Meta Analysis ◽

Grey Literature ◽

Cochrane Central Register ◽

Randomised Trials ◽

Eligibility Criteria ◽

The Impact

ABSTRACTObjectiveTo determine the impact of mesenchymal stromal cells outcomes important to patients with COVID-19.DesignThis is the protocol of a living systematic review.Data sourcesWe will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralised repository in L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customised to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal.Eligibility criteria for selecting studies and methodsWe adapted an already published common protocol for multiple parallel systematic reviews to the specificities of this question.We will include randomised trials evaluating the effect of mesenchymal stromal cells versus placebo or no treatment in patients with COVID-19. Randomised trials evaluating other coronavirus infections, such as MERS-CoV and SARS-CoV, and non-randomised studies in COVID-19 will be searched in case we find no direct evidence from randomised trials, or if the direct evidence provides low- or very low-certainty for critical outcomes.Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will pool the results using meta-analysis and will apply the GRADE system to assess the certainty of the evidence for each outcome.A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates.Ethics and disseminationNo ethics approval is considered necessary. The results of this review will be widely disseminated via peer-reviewed publications, social networks and traditional media.PROSPERO RegistrationSubmitted to PROSPERO (awaiting ID allocation).

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Alloreactive Immune Response Associated to Human Mesenchymal Stromal Cells Treatment: A Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm10132991 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2991

Author(s):

Raquel Sanabria-de la Torre ◽

María I. Quiñones-Vico ◽

Ana Fernández-González ◽

Manuel Sánchez-Díaz ◽

Trinidad Montero-Vílchez ◽

...

Keyword(s):

Systematic Review ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Immune Rejection ◽

Human Mesenchymal Stromal Cells ◽

Immunological Profile ◽

Tolerability Data ◽

Donor Specific Antibodies ◽

The Impact ◽

Hla Mismatches

The well-known immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) are the reason why they are being used for the treatment of many diseases. Because they are considered hypoimmunogenic, MSCs treatments are performed without considering histocompatibility barriers and without anticipating possible immune rejections. However, recent preclinical studies describe the generation of alloantibodies and the immune rejection of MSCs. This has led to an increasing number of clinical trials evaluating the immunological profile of patients after treatment with MSCs. The objective of this systematic review was to evaluate the generation of donor specific antibodies (DSA) after allogeneic MSC (allo-MSC) therapy and the impact on safety or tolerability. Data from 555 patients were included in the systematic review, 356 were treated with allo-MSC and the rest were treated with placebo or control drugs. A mean of 11.51% of allo-MSC-treated patients developed DSA. Specifically, 14.95% of these patients developed DSA and 6.33% of them developed cPRA. Neither the production of DSA after treatment nor the presence of DSA at baseline (presensitization) were correlated with safety and/or tolerability of the treatment. The number of doses administrated and human leucocyte antigen (HLA) mismatches between donor and recipient did not affect the production of DSA. The safety of allo-MSC therapy has been proved in all the studies and the generation of alloantibodies might not have clinical relevance. However, there are very few studies in the area. More studies with adequate designs are needed to confirm these results.

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Biodistribution of Mesenchymal Stromal Cells after Administration in Animal Models and Humans: A Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm10132925 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2925

Author(s):

Manuel Sanchez-Diaz ◽

Maria I. Quiñones-Vico ◽

Raquel Sanabria de la Torre ◽

Trinidad Montero-Vílchez ◽

Alvaro Sierra-Sánchez ◽

...

Keyword(s):

Animal Models ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Cellular Therapy ◽

The Body ◽

Intralesional Injection ◽

Intraarterial Infusion ◽

Routes Of Administration ◽

Administration Routes

Mesenchymal Stromal Cells (MSCs) are of great interest in cellular therapy. Different routes of administration of MSCs have been described both in pre-clinical and clinical reports. Knowledge about the fate of the administered cells is critical for developing MSC-based therapies. The aim of this review is to describe how MSCs are distributed after injection, using different administration routes in animal models and humans. A literature search was performed in order to consider how MSCs distribute after intravenous, intraarterial, intramuscular, intraarticular and intralesional injection into both animal models and humans. Studies addressing the biodistribution of MSCs in “in vivo” animal models and humans were included. After the search, 109 articles were included in the review. Intravenous administration of MSCs is widely used; it leads to an initial accumulation of cells in the lungs with later redistribution to the liver, spleen and kidneys. Intraarterial infusion bypasses the lungs, so MSCs distribute widely throughout the rest of the body. Intramuscular, intraarticular and intradermal administration lack systemic biodistribution. Injection into various specific organs is also described. Biodistribution of MSCs in animal models and humans appears to be similar and depends on the route of administration. More studies with standardized protocols of MSC administration could be useful in order to make results homogeneous and more comparable.

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Evaluating the effectiveness of interventions to reducing screen time in children: meta-analysis of randomized controlled trials

Journal of Public Mental Health ◽

10.1108/jpmh-03-2021-0039 ◽

2021 ◽

Vol ahead-of-print (ahead-of-print) ◽

Author(s):

Duygu Akçay ◽

Nuray Barış

Keyword(s):

Effect Size ◽

Subgroup Analysis ◽

Screen Time ◽

Meta Analysis ◽

Intervention Group ◽

Evidence Base ◽

Control Group ◽

Content Type ◽

Mean Differences ◽

The Impact

Purpose The purpose of this paper is to evaluate the impact of interventions focused on reducing screen time in children. Design/methodology/approach Studies that aim to investigate the effects of interventions aimed at reducing the time spent in front of the screen (i.e. screen time). A Random-effects model was used to calculate the pooled standard mean differences. The outcome was to evaluate the screen time in children in the 0–18 age range. A subgroup analysis was performed to reveal the extent to which the overall effect size varied by subgroups (participant age, duration of intervention and follow). Findings For the outcome, the meta-analysis included 21 studies, and the standard difference in mean change in screen time in the intervention group compared with the control group was −0.16 (95% confidence interval [CI], −0.21 to −0.12) (p < 0.001). The effect size was found to be higher in long-term (=7 months) interventions and follow-ups (p < 0.05). Originality/value Subgroup analysis showed that a significant effect of screen time reduction was observed in studies in which the duration of intervention and follow-up was =7 months. As the evidence base grows, future researchers can contribute to these findings by conducting a more comprehensive analysis of effect modifiers and optimizing interventions to reduce screen time.

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Reliability of Computerized Neurocognitive Tests for Concussion Assessment: A Meta-Analysis

Journal of Athletic Training ◽

10.4085/1062-6050-52.6.03 ◽

2017 ◽

Vol 52 (9) ◽

pp. 826-833 ◽

Cited By ~ 24

Author(s):

James L. Farnsworth ◽

Lucas Dargo ◽

Brian G. Ragan ◽

Minsoo Kang

Keyword(s):

Correlation Coefficient ◽

Intraclass Correlation Coefficient ◽

Effect Size ◽

Sampling Error ◽

Meta Analysis ◽

Intraclass Correlation ◽

Cognitive Testing ◽

Test Duration ◽

Neurocognitive Tests ◽

The Impact

Objective: Although widely used, computerized neurocognitive tests (CNTs) have been criticized because of low reliability and poor sensitivity. A systematic review was published summarizing the reliability of Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scores; however, this was limited to a single CNT. Expansion of the previous review to include additional CNTs and a meta-analysis is needed. Therefore, our purpose was to analyze reliability data for CNTs using meta-analysis and examine moderating factors that may influence reliability. Data Sources: A systematic literature search (key terms: reliability, computerized neurocognitive test, concussion) of electronic databases (MEDLINE, PubMed, Google Scholar, and SPORTDiscus) was conducted to identify relevant studies. Study Selection: Studies were included if they met all of the following criteria: used a test-retest design, involved at least 1 CNT, provided sufficient statistical data to allow for effect-size calculation, and were published in English. Data Extraction: Two independent reviewers investigated each article to assess inclusion criteria. Eighteen studies involving 2674 participants were retained. Intraclass correlation coefficients were extracted to calculate effect sizes and determine overall reliability. The Fisher Z transformation adjusted for sampling error associated with averaging correlations. Moderator analyses were conducted to evaluate the effects of the length of the test-retest interval, intraclass correlation coefficient model selection, participant demographics, and study design on reliability. Heterogeneity was evaluated using the Cochran Q statistic. Data Synthesis: The proportion of acceptable outcomes was greatest for the Axon Sports CogState Test (75%) and lowest for the ImPACT (25%). Moderator analyses indicated that the type of intraclass correlation coefficient model used significantly influenced effect-size estimates, accounting for 17% of the variation in reliability. Conclusions: The Axon Sports CogState Test, which has a higher proportion of acceptable outcomes and shorter test duration relative to other CNTs, may be a reliable option; however, future studies are needed to compare the diagnostic accuracy of these instruments.

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Efectos de la intervención en conciencia morfológica sobre la lectura, escritura y comprensión: Meta-análisis

Anales de Psicología ◽

10.6018/analesps.32.1.196261 ◽

2015 ◽

Vol 32 (1) ◽

pp. 60 ◽

Cited By ~ 2

Author(s):

Mercedes I. Rueda-Sánchez ◽

Patricia López-Bastida

Keyword(s):

Effect Size ◽

Selection Criteria ◽

Meta Analysis ◽

Reading Difficulties ◽

Morphological Awareness ◽

Awareness Training ◽

Moderating Variables ◽

Reading Vocabulary ◽

Morphological Awareness Training ◽

The Impact

The aim is to check, through a meta-analysis, the impact of morphological awareness training on writing, reading, comprehension and vocabulary of grade schooler. 31 studies were included in the meta-analysis; they were obtained from 19 articles that meet the selection criteria. Morphological awareness instruction has a high-medium and significant effect size in studied variables of literacy. On writing, g=0.491, SE=0.078, IQ=0339-0643, p=.000, reading, g=0.473, SE=0.096, IQ=0284-0662, p=.000, comprehension, g=0.468, SE=0.123, IQ=0227-0708, p= .000 and finally vocabulary, g=0.501, SE=0.152, IQ=0203-0798, p= .001. The test of Heterogeneity Q is only significant on writing so other moderating variables were explored but no differences between groups were found. It shows morphological awareness training improves reading, vocabulary and comprehension of grade schooler with and without reading difficulties. Nevertheless, the results on writing are more heterogeneous.

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Mesenchymal Stromal Cells Derived Conditioned Medium in Pulmonary Fibrosis: A Systematic Review and Meta-analysis

Archives of Iranian Medicine ◽

10.34172/aim.2020.116 ◽

2020 ◽

Vol 23 (12) ◽

pp. 870-879

Author(s):

Kosar Mohamed Ali ◽

Fattah Hama Rahim Fattah ◽

Shirwan Hamasalh Omar ◽

Mohammed I M Gubari ◽

Mahmoud Yousefifard ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Conditioned Medium ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Interleukin 6 ◽

Meta Analysis ◽

Type Iii Collagen ◽

Type I ◽

Collagen Deposition ◽

Tgf Β1

Background: A definitive conclusion on the efficacy of mesenchymal stromal cells-derived conditioned medium (MSCs-CM) in pulmonary fibrosis has not yet been reached. Therefore, the present meta-analysis intends to investigate the efficacy of MSCs-CM administration on improvement of pulmonary fibrosis. Methods: An extensive search was performed on the Medline, Embase, Scopus and Web of Science databases by the end of August 2019. Outcomes in the present study included pulmonary fibrosis score, lung collagen deposition, lung collagen expression, transforming growth factor β1 (TGF-β1) expression and interleukin-6 expression. Finally, the data were pooled and an overall standardized mean difference (SMD) with a 95% confidence interval (CI) was reported. Results: Data from seven studies were included. Analyses showed that administration of MSCs-CM significantly improved pulmonary fibrosis (SMD = -2.36; 95% CI: -3.21, -1.51). MSCs-CM administration also attenuated lung collagen deposition (SMD = -1.70; 95% CI: -2.18, -1.23) and decreased expression of type I collagen (SMD = -6.27; 95% CI: -11.00, -1.55), type III collagen (SMD = -5.16; 95% CI: -9.86, -0.47), TGF- β1 (SMD = -3.36; 95% CI: - 5.62, -1.09) and interleukin-6 (SMD = -1.69; 95% CI: - 3.14, -0.24). Conclusion: The present meta-analysis showed that administration of MSCs-CM improves pulmonary fibrosis. It seems that the effect of MSCs-CM was mediated by reducing collagen deposition as well as inhibiting the production of inflammatory chemokines such as TGF-β1 and interleukin 6 (IL-6). Since there is no evidence on the efficacy of MSCs-CM in large animals, further studies are needed to translate the finding to clinical studies.

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