scholarly journals Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Aleksandra Kaliszewska ◽  
Joseph Allison ◽  
Tarik-Tarkan Col ◽  
Christopher Shaw ◽  
Natalia Arias
Keyword(s):  
Meta Analysis ◽  
Neuronal Loss ◽  
Synaptic Dysfunction ◽  
Protein Levels ◽  
Hexanucleotide Repeat ◽  
Gene Dysregulation ◽  
Rna Foci ◽  
Synaptic Neurotransmission ◽  
Meta Analyses ◽  
And Control

AbstractA hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with synaptic dysfunction identified as an early pathological hallmark. Although TDP-43 pathology and overt neurodegeneration are largely absent from the cerebellum, the pathological hallmarks of RNA foci and dipeptide repeat protein (DPR) inclusions are most abundant. Here, we present a systematic literature search in the databases of PubMed, Scopus, Embase, Web of Science and Science Direct up until March 5, 2021, which yielded 19,515 publications. Following the exclusion criteria, 72 articles were included having referred to C9orf72, synapses and the cerebellum. Meta-analyses were conducted on studies which reported experimental and control groups with means and standard deviations extracted from figures using the online tool PlotDigitizer. This revealed dendritic defects (P = 0.03), reduced C9orf72 in human patients (P = 0.005) and DPR-related neuronal loss (P = 0.0006) but no neuromuscular junction abnormalities (P = 0.29) or cerebellar neuronal loss (P = 0.23). Our results suggest that dendritic arborisation defects, synaptic gene dysregulation and altered synaptic neurotransmission may drive cerebellar synaptic dysfunction in C9-ALS/FTD. In this review, we discuss how the chronological appearance of the different pathological hallmarks alters synaptic integrity which may have profound implications for disease progression. We conclude that a reduction in C9orf72 protein levels combined with the accumulation of RNA foci and DPRs act synergistically to drive C9 synaptopathy in the cerebellum of C9-ALS/FTD patients.

scholarly journals 10 Years of Pulsed-Xenon Ultraviolet Disinfection

2020 ◽  
Vol 41 (S1) ◽  
pp. s438-s438
Author(s):  
Mark Stibich ◽  
Sarah Simmons ◽  
Deborah Passey
Keyword(s):  
Relative Risk ◽  
Meta Analysis ◽  
Outcome Studies ◽  
Uv Disinfection ◽  
Clostridioides Difficile ◽  
Environmental Effectiveness ◽  
Meta Analyses ◽  
Hospital Acquired ◽  
And Control ◽  
Effectiveness Studies

Background: Ultraviolet light (UV) disinfection using low-pressure mercury lamps has been around since the 1940s. The advent of pulsed-xenon UV for hospital use in 2010 has provided a nontoxic and novel technology for hospital disinfection with the first data presented at the 2010 SHEA Decennial. The purpose of this systematic review and meta-analysis is to examine the current body of evidence for pulsed xenon UV disinfection. Methods: The literature search criteria included the following: research conducted in domestic and international settings using pulsed-xenon for surface disinfection, published between 2000 and 2019, and reporting on environmental effectiveness or hospital-acquired reductions (HAIs). We searched PubMed, Google Scholar, and Web of Science. The meta-analysis included 24 studies: 12 HAI outcome studies and 12 environmental effectiveness studies. Meta-analyses were conducted by calculating the percentage reductions for environmental effectiveness, and for the HAI outcome studies, we used a random-effects model to pool the relative risk of HAI. The outcome studies used 272 and 299 months of data for the experimental and control groups, respectively. Results: There was an overall benefit of using pulsed-xenon UV. The overall relative risk of infection decreased compared to the control arm (RR, 0.64; 95% CI, 0.54–0.76). The percentage reductions in environmental studies were as follows: Clostridioides difficile (94.8%), methicillin-resistant Staphylococcus aureus (91.5%), vancomycin-resistant Enterococcus (99.2%), and aerobic bacteria (94.2%). Conclusions: Overall, pulsed-xenon UV was effective for reducing environmental contamination and had the ability to significantly reduce HAIs.Funding: Xenex, Inc., funded this study.Disclosures: Mark Stibich receives a salary from Xenex and is a shareholder of Xenex. Deborah Passey receives a salary from Xenex Disinfection Services.

Interventions for Adolescents With ADHD to Improve Peer Social Functioning: A Systematic Review and Meta-Analysis

2020 ◽  
pp. 108705472090651 ◽  
Author(s):  
Sarah Morris ◽  
Jade Sheen ◽  
Mathew Ling ◽  
Denise Foley ◽  
Emma Sciberras
Keyword(s):  
Social Functioning ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Parent Report ◽  
Self Report ◽  
Age Group ◽  
Control Groups ◽  
Social Interventions ◽  
Meta Analyses ◽  
And Control

Objective: Peer social functioning difficulties characteristic of ADHD persist into adolescence, but the efficacy of interventions for this age group remains unclear. Method: A systematic search of nonpharmacological interventions for adolescents with ADHD (10–18 years) identified 11 trials addressing social functioning, of which eight were included in meta-analyses. Results: Random effects meta-analyses of four randomized trials found no differences in social functioning between treatment and control groups by parent- ( g = −0.08 [−0.34, 0.19], k = 4, N = 354) or teacher-report ( g = 0.17 [−0.06, 0.40], k = 3, N = 301). Meta-analyses of nonrandomized studies indicated participants’ social functioning improved from baseline to postintervention by parent-report, but not teacher- or self-report. All trials had a high risk of bias. Conclusion: These results highlight the paucity of research in this age group. There is little evidence that current interventions improve peer social functioning. Clearer conceptualizations of developmentally relevant targets for remediation may yield more efficacious social interventions.

scholarly journals Estimation in meta-analyses of response ratios

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ilyas Bakbergenuly ◽  
David C. Hoaglin ◽  
Elena Kulinskaya
Keyword(s):  
Meta Analysis ◽  
Weighted Average ◽  
Effective Sample Size ◽  
Logarithmic Scale ◽  
Response Ratio ◽  
Effect Measure ◽  
Interval Estimators ◽  
Point Estimators ◽  
Meta Analyses ◽  
And Control

Abstract Background For outcomes that studies report as the means in the treatment and control groups, some medical applications and nearly half of meta-analyses in ecology express the effect as the ratio of means (RoM), also called the response ratio (RR), analyzed in the logarithmic scale as the log-response-ratio, LRR. Methods In random-effects meta-analysis of LRR, with normal and lognormal data, we studied the performance of estimators of the between-study variance, τ2, (measured by bias and coverage) in assessing heterogeneity of study-level effects, and also the performance of related estimators of the overall effect in the log scale, λ. We obtained additional empirical evidence from two examples. Results The results of our extensive simulations showed several challenges in using LRR as an effect measure. Point estimators of τ2 had considerable bias or were unreliable, and interval estimators of τ2 seldom had the intended 95% coverage for small to moderate-sized samples (n<40). Results for estimating λ differed between lognormal and normal data. Conclusions For lognormal data, we can recommend only SSW, a weighted average in which a study’s weight is proportional to its effective sample size, (when n≥40) and its companion interval (when n≥10). Normal data posed greater challenges. When the means were far enough from 0 (more than one standard deviation, 4 in our simulations), SSW was practically unbiased, and its companion interval was the only option.

scholarly journals A systematic review and meta-analysis of randomized controlled trials for the reduction of surgical site infection in closed incision management versus standard of care dressings over closed vascular groin incisions

Vascular ◽  
2020 ◽  
Vol 28 (3) ◽  
pp. 274-284 ◽  
Author(s):  
Alexander Gombert ◽  
Ellen Dillavou ◽  
Ralph D’Agostino ◽  
Leah Griffin ◽  
Julie M Robertson ◽  
...  
Keyword(s):  
Vascular Surgery ◽  
Surgical Site Infection ◽  
Meta Analysis ◽  
Site Infection ◽  
Infection Rates ◽  
Control Groups ◽  
Randomized Controlled ◽  
Risk Patients ◽  
Meta Analyses ◽  
And Control

Objective Surgical site infection after groin incision is a common complication and a financial burden to patients and healthcare systems. Closed incision negative pressure therapy (ciNPT) has been associated with decreased surgical site infection rates in published literature. This meta-analysis examines the effect of ciNPT (PREVENA™ Incision Management System; KCI, San Antonio, TX) versus traditional postsurgical dressing use in reducing surgical site infection rates over closed groin incisions following vascular surgery. Methods A systematic literature search using PubMed, OVID, EMBASE, and QUOSA was performed on 3 January 2019, by two independent researchers and focused on publications between 1 January 2005 and 31 December 2018. The review conformed to the statement and reporting check list of the Preferred Reporting Items for Systematic Reviews and Meta Analyses. Inclusion criteria included abstract or manuscript written in English, published studies, conference abstracts, randomized controlled trials (RCTs), ciNPT usage over closed groin incisions in vascular surgery, comparison of ciNPT use and traditional dressings, study endpoint/outcome of surgical site infection, and study population of >10. Characteristics of study participants, surgical procedure, type of dressing used, duration of treatment, incidence of surgical site infection, and length of follow-up were extracted. Weighted odds ratios and 95% confidence intervals were calculated to pool study and control groups in each publication for analysis. Treatment effects were combined using Mantel-Haenszel risk ratios, and the Chi-Square test was used to assess heterogeneity. Overall, high-risk patients, normal-risk patients, and Szilagyi I, II, III outcomes were assessed between ciNPT and control groups. The Cochrane Collaboration tool was utilized to assess the risk of bias for all studies included in the analysis. Results A total of 615 articles were identified from the literature search. After removal of excluded studies and duplicates, six RCT studies were available for analysis. In these studies, a total of 362 patients received ciNPT, and 371 patients received traditional dressings (control). Surgical site infection events occurred in 41 ciNPT patients and 107 control patients. The heterogeneity test was nonsignificant ( p > 0.05). The overall RCT meta-analysis showed a highly significant effect in favor of ciNPT (OR = 3.06, 95% CI [2.05, 4.58], p < 0.05). High-risk, normal-risk, Szilagyi I, and Szilagyi II meta-analyses were also statistically significant in favor of ciNPT use ( p < 0.05). The varying RCT inclusion/exclusion criteria, such as differences in procedure types, and patient populations form the major limitations of this study. Conclusions A statistically significant reduction in the incidence of surgical site infection was seen following ciNPT usage in patients undergoing vascular surgery with groin incisions.

scholarly journals Blood-Based ATN Biomarkers of Alzheimer’s Disease: A Meta-Analysis

2021 ◽  
Vol 79 (1) ◽  
pp. 177-195
Author(s):  
Ivan Koychev ◽  
Katrin Jansen ◽  
Alina Dette ◽  
Liu Shi ◽  
Heinz Holling
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Meta Analysis ◽  
Random Effect ◽  
Neurofilament Light ◽  
Meta Analyses ◽  
And Control ◽  
T Tau ◽  
Biological State

Background: The Amyloid Tau Neurodegeneration (ATN) framework was proposed to define the biological state underpinning Alzheimer’s disease (AD). Blood-based biomarkers offer a scalable alternative to the costly and invasive currently available biomarkers. Objective: In this meta-analysis we sought to assess the diagnostic performance of plasma amyloid (Aβ40, Aβ42, Aβ42/40 ratio), tangle (p-tau181), and neurodegeneration (total tau [t-tau], neurofilament light [NfL]) biomarkers. Methods: Electronic databases were screened for studies reporting biomarker concentrations for AD and control cohorts. Biomarker performance was examined by random-effect meta-analyses based on the ratio between biomarker concentrations in patients and controls. Results: 83 studies published between 1996 and 2020 were included in the analyses. Aβ42/40 ratio as well as Aβ42 discriminated AD patients from controls when using novel platforms such as immunomagnetic reduction (IMR). We found significant differences in ptau-181 concentration for studies based on single molecule array (Simoa), but not for studies based on IMR or ELISA. T-tau was significantly different between AD patients and control in IMR and Simoa but not in ELISA-based studies. In contrast, NfL differentiated between groups across platforms. Exosome studies showed strong separation between patients and controls for Aβ42, t-tau, and p-tau181. Conclusion: Currently available assays for sampling plasma ATN biomarkers appear to differentiate between AD patients and controls. Novel assay methodologies have given the field a significant boost for testing these biomarkers, such as IMR for Aβ, Simoa for p-tau181. Enriching samples through extracellular vesicles shows promise but requires further validation.

scholarly journals BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Esteban Quezada ◽  
Claudio Cappelli ◽  
Iván Diaz ◽  
Nur Jury ◽  
Nicholas Wightman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Protein Levels ◽  
Hexanucleotide Repeat ◽  
Rna Foci ◽  
Behavioral Abnormalities ◽  
Bet Inhibitors

Abstract Background An intronic GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), referred to as C9ALS/FTD. No cure or effective treatment exist for C9ALS/FTD. Three major molecular mechanisms have emerged to explain C9ALS/FTD disease mechanisms: (1) C9ORF72 loss-of-function through haploinsufficiency, (2) dipeptide repeat (DPR) proteins mediated toxicity by the translation of the repeat RNAs, and more controversial, (3) RNA-mediated toxicity by bidirectional transcription of the repeats that form intranuclear RNA foci. Recent studies indicate a double-hit pathogenic mechanism in C9ALS/FTD, where reduced C9ORF72 protein levels lead to impaired clearance of toxic DPRs. Here we explored whether pharmacological compounds can revert these pathological hallmarks in vitro and cognitive impairment in a C9ALS/FTD mouse model (C9BAC). We specifically focused our study on small molecule inhibitors targeting chromatin-regulating proteins (epidrugs) with the goal of increasing C9ORF72 gene expression and reduce toxic DPRs. Results We generated luciferase reporter cell lines containing 10 (control) or ≥ 90 (mutant) G4C2 HRE located between exon 1a and 1b of the human C9ORF72 gene. In a screen of 14 different epidrugs targeting bromodomains, chromodomains and histone-modifying enzymes, we found that several bromodomain and extra-terminal domain (BET) inhibitors (BETi), including PFI-1 and JQ1, increased luciferase reporter activity. Using primary cortical cultures from C9BAC mice, we further found that PFI-1 treatment increased the expression of V1-V3 transcripts of the human mutant C9ORF72 gene, reduced poly(GP)-DPR inclusions but enhanced intranuclear RNA foci. We also tested whether JQ1, an BETi previously shown to reach the mouse brain by intraperitoneal (i.p.) injection, can revert behavioral abnormalities in C9BAC mice. Interestingly, it was found that JQ1 administration (daily i.p. administration for 7 days) rescued hippocampal-dependent cognitive deficits in C9BAC mice. Conclusions Our findings place BET bromodomain inhibitors as a potential therapy for C9ALS/FTD by ameliorating C9ORF72-associated pathological and behavioral abnormalities. Our finding that PFI-1 increases accumulation of intranuclear RNA foci is in agreement with recent data in flies suggesting that nuclear RNA foci can be neuroprotective by sequestering repeat transcripts that result in toxic DPRs.

scholarly journals Interactive Features of E-Texts’ Effects on Learning: A Systematic Review and Meta-analysis

2021 ◽  
Author(s):  
Virginia Clinton-Lisell
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Reading Performance ◽  
Systematic Search ◽  
Future Directions ◽  
Positive Effects ◽  
Collaborative Tools ◽  
Meta Analyses ◽  
And Control

E-texts afford interactive features that are not feasible with paper texts. Several studies have been conducted examining interactive features of e-texts, but it is uncertain what the overall effect is or what features may be most useful. The purpose of this study is to systematically review and meta-analyze the findings comparing reading performance and/or reading times between e-texts with interactive features and control texts (paper or static e-texts). The systematic search of the literature identified 26 independent studies on reading performance. Based on the meta-analyses, interactive features benefited reading performance (g = .66, p &lt; .001). Individual studies with positive effects involved multiple interactive features; however, potential contributions of three types of features (questions with feedback, digital glossaries, and collaborative tools) are discussed. Future directions for examining interactive features experimentally to better understand what features are most helpful for whom are described.

scholarly journals Periodontal Outcomes in Liver Transplantation Individuals: A Systematic Review and Meta-analysis

2021 ◽  
Vol 30 (1) ◽  
pp. 122-131
Author(s):  
Tuélita Marques Galdino ◽  
Carla Souza Oliveira ◽  
Allyson Nogueira Moreira ◽  
Francisco Ivison Rodrigues Limeira ◽  
Cláudia Silami Magalhães ◽  
...  
Keyword(s):  
Alveolar Bone ◽  
Meta Analysis ◽  
Grey Literature ◽  
Mean Difference ◽  
Control Group ◽  
Clinical Attachment Level ◽  
Probing Depth ◽  
Meta Analyses ◽  
And Control ◽  
Attachment Level

Aim: To systematically review the literature for observational studies evaluating periodontal outcomes in pre- and post-liver transplant (LT) individuals compared to a control group. Methods: Specific strategies were designed to search five databases and the grey literature. Hand-searches were also performed. The following periodontal outcomes were analyzed in pre-LT, post-LT and control groups: plaque index (PI), gingival index (GI), gingival growth (GO), alveolar bone loss (ABL) probing depth (PD) and clinical attachment level (CAL). Meta-analyses and subgroup analyses were conducted. Results: Among the 257 studies retrieved, 11 studies were included. Four studies were incorporated into the meta-analysis and showed that PI (mean difference=0.15, 95%CI: 0.12-0.18) and GI (mean difference=0.31, 95%CI: 0.06-0.56) were significantly higher in post-LT individuals compared to the control group. There was no significant mean difference of PD (mean difference=0.49, 95%CI: -0.26-1.25) but CAL (mean differ- ence=1.47, 95%CI: 0.19-2.75) were significantly higher in pre-LT individuals compared to the control group. Conclusion: The higher means of PI and GI in post-LT and CAL in pre-LT compared to healthy individuals suggest a relationship between the periodontal condition and the transplantation status.

scholarly journals Large scale meta-analysis of preclinical toxicity data for target characterisation and hypotheses generation

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252533
Author(s):  
Jordi Munoz-Muriedas
Keyword(s):  
Animal Studies ◽  
Large Scale ◽  
Meta Analysis ◽  
Preclinical Studies ◽  
Technological Advances ◽  
Consistent Manner ◽  
Critical Components ◽  
Meta Analyses ◽  
And Control

Recent technological advances in the field of big data have increased our capabilities to query large databases and combine information from different domains and disciplines. In the area of preclinical studies, initiatives like SEND (Standard for Exchange of Nonclinical Data) will also contribute to collect and present nonclinical data in a consistent manner and increase analytical possibilities. With facilitated access to preclinical data and improvements in analytical algorithms there will surely be an expectation for organisations to ensure all the historical data available to them is leveraged to build new hypotheses. These kinds of analyses may soon become as important as the animal studies themselves, in addition to being critical components to achieve objectives aligned with 3Rs. This article proposes the application of meta-analyses at large scale in corporate databases as a tool to exploit data from both preclinical studies and in vitro pharmacological activity assays to identify associations between targets and tissues that can be used as seeds for the development of causal hypotheses to characterise of targets. A total of 833 in-house preclinical toxicity studies relating to 416 compounds reported to be active (pXC50 ≥ 5.5) against a panel of 96 selected targets of interest for potential off-target non desired effects were meta-analysed, aggregating the data in tissue–target pairs. The primary outcome was the odds ratio (OR) of the number of animals with observed events (any morphology, any severity) in treated and control groups in the tissue analysed. This led to a total of 2139 meta-analyses producing a total of 364 statistically significant associations (random effects model), 121 after adjusting by multiple comparison bias. The results show the utility of the proposed approach to leverage historical corporate data and may offer a vehicle for researchers to share, aggregate and analyse their preclinical toxicological data in precompetitive environments.

scholarly journals Acupuncture or Acupressure at the Sanyinjiao (SP6) Acupoint for the Treatment of Primary Dysmenorrhea: A Meta-Analysis

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ma-Na Chen ◽  
Li-Wei Chien ◽  
Chi-Feng Liu
Keyword(s):  
Randomized Controlled Trials ◽  
Lower Limit ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Primary Dysmenorrhea ◽  
Randomized Controlled ◽  
Upper Limit ◽  
The Mean ◽  
Meta Analyses ◽  
And Control

This meta-analysis aimed to evaluate the effectiveness of acupuncture or acupressure at the Sanyinjiao (SP6) acupoint in relieving pain associated with primary dysmenorrhea. We searched the scientific literature databases to identify randomized controlled trials. The primary outcome was visual analogue scale (VAS) pain score. Three acupuncture and four acupressure trials were included in the meta-analyses. For the acupuncture analysis, there was no difference in the mean VAS score reduction between the SP6 acupoint and control (GB39 acupoint) groups (−4.935; lower limit = −15.757, upper limit = 5.887;P=0.371). For the acupressure analysis, there was a significant difference in the mean VAS score after intervention between the SP6 acupoint and control (rest/light touch at SP6/nonacupoint acupressure) groups, favoring the SP6 acupoint group (−1.011; lower limit = −1.622, upper limit = −0.400;P=0.001). Sensitivity analyses demonstrated good reliability of the meta-analyses findings. These findings suggest that acupuncture at SP6 is not more effective than acupuncture at an unrelated acupoint in the relief from primary dysmenorrhea. Acupressure at SP6 may be effective in the relief from primary dysmenorrhea. High-quality randomized controlled trials are needed to confirm these findings.

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