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The Cochrane Database of Systematic... May 2018Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a number of pharmacological therapies have been investigated as potential treatments for apathy in AD.
OBJECTIVES
Objective 1: To assess the safety and efficacy of pharmacotherapies for the treatment of apathy in Alzheimer's disease (AD).Objective 2: To assess the effect on apathy of pharmacotherapies investigated for other primary outcomes in the treatment of AD.
SEARCH METHODS
We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) portal, ICTRP on 17 May 2017.
SELECTION CRITERIA
Eligible studies were double-blind, randomized, placebo-controlled trials (RCTs) investigating apathy as a primary or secondary outcome in people with AD.
DATA COLLECTION AND ANALYSIS
Three review authors extracted data. We assessed the risks of bias of included studies using Cochrane methods, and the overall quality of evidence for each outcome using GRADE methods. We calculated mean difference (MD), standardized mean difference (SMD) or risk ratio (RR) with 95% confidence intervals on an intention-to-treat basis for all relevant outcome measures.
MAIN RESULTS
We included 21 studies involving a total of 6384 participants in the quantitative analyses. Risk of bias is very low to moderate. All studies reported appropriate methods of randomization and blinding. Most studies reported appropriate methods of allocation concealment. Four studies, three with methylphenidate and one with modafinil, had a primary aim of improving apathy. In these studies, all participants had clinically significant apathy at baseline. Methylphenidate may improve apathy compared to placebo. This finding was present when apathy was assessed using the apathy evaluation scale (AES), which was used by all three studies investigating methylphenidate: MD -4.99, 95% CI -9.55 to -0.43, n = 145, 3 studies, low quality of evidence, but not when assessed with the neuropsychiatric inventory (NPI)-apathy subscale, which was used by two of the three studies investigating methylphenidate: MD -0.08, 95% CI -3.85 to 3.69, n = 85, 2 studies, low quality of evidence. As well as having potential benefits for apathy, methylphenidate probably also slightly improves cognition (MD 1.98, 95% CI 1.06 to 2.91, n = 145, 3 studies, moderate quality of evidence), and probably improves instrumental activities of daily living (MD 2.30, 95% CI 0.74 to 3.86, P = 0.004, n = 60, 1 study, moderate quality of evidence), compared to placebo. There may be no difference between methylphenidate and placebo in the risk of developing an adverse event: RR 1.28, 95% CI 0.67 to 2.42, n = 145, 3 studies, low quality of evidence. There was insufficient evidence from one very small study of modafinil to determine the effect of modafinil on apathy assessed with the FrSBe-apathy subscale: MD 0.27, 95% CI -3.51 to 4.05, n = 22, 1 study, low quality of evidence. In all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. We considered the evidence on apathy from these studies to be indirect and associated with publication bias. There was low or very low quality of evidence on cholinesterase inhibitors (ChEIs) (six studies), ChEI discontinuation (one study), antipsychotics (two studies), antipsychotic discontinuation (one study), antidepressants (two studies), mibampator (one study), valproate (three studies) and semagacestat (one study).
AUTHORS' CONCLUSIONS
Methylphenidate may demonstrate a benefit for apathy and may have slight benefits for cognition and functional performance in people with AD, but this finding is associated with low-quality evidence. Our meta-analysis is limited by the small number of studies within each drug class, risk of bias, publication bias, imprecision and inconsistency between studies. Additional studies should be encouraged targeting people with AD with clinically significant apathy which investigate apathy as a primary outcome measure, and which have a longer duration and a larger sample size. This could increase the quality of evidence for methylphenidate, and may confirm whether or not it is an effective pharmacotherapy for apathy in AD.
Topics: Alanine; Alzheimer Disease; Antidepressive Agents; Apathy; Azepines; Benzhydryl Compounds; Biphenyl Compounds; Central Nervous System Stimulants; Cholinesterase Inhibitors; Humans; Methylphenidate; Modafinil; Randomized Controlled Trials as Topic; Sulfonamides; Valproic Acid
PubMed: 29727467
DOI: 10.1002/14651858.CD012197.pub2 -
Techniques in Coloproctology Jul 2018The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for... (Review)
Review
The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples.
Topics: Adult; Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; Early Detection of Cancer; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Neoplasm Staging; Prospective Studies; RNA, Long Noncoding; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Septins; Syndecan-2
PubMed: 30022330
DOI: 10.1007/s10151-018-1820-3 -
Frontiers in Oncology 2022Pediatric and adult K27M-mutant midline gliomas have variable clinical presentations, prognoses, and molecular backgrounds. In this study, we integrated data from...
INTRODUCTION
Pediatric and adult K27M-mutant midline gliomas have variable clinical presentations, prognoses, and molecular backgrounds. In this study, we integrated data from published studies to investigate the differences between these two groups.
METHODS
PubMed and Web of Science were searched for potential data. Studies were included if they had available individual participant data on patients age of K27M-mutant midline gliomas. For time-to-event analyses, Kaplan-Meier analysis and Cox regression models were carried out; corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of age and clinical covariates on progression-free survival (PFS) and overall survival (OS).
RESULTS
We included 43 studies comprising 272 adults and 657 pediatric midline gliomas with K27M mutation for analyses. In adults, there was a male predilection whereas females were slightly more common than males in the pediatric group. Spinal cord tumors were more frequent in adults. The prevalence of K27M mutation was significantly higher in the pediatric cohort. Compared to adult patients, pediatric K27M-mutant midline gliomas exhibited more aggressive features including higher rates of pathologic features of high-grade tumors and Ki67 proliferation index, and had a shorter PFS and OS. Genetically, mutations were more common whereas methylation, , and mutations were less prevalent in the pediatric cohort.
CONCLUSION
Pediatric K27M-mutant midline gliomas were demographically, clinically, and molecularly distinct from adult patients, highlighting an opportunity to refine the risk stratification for these neoplasms.
PubMed: 35371982
DOI: 10.3389/fonc.2022.858148 -
Journal of Clinical Anesthesia Nov 2023The objective of this systematic review was to estimate the relative risk of prolonged times to tracheal extubation with desflurane versus sevoflurane or isoflurane.... (Meta-Analysis)
Meta-Analysis Review
The objective of this systematic review was to estimate the relative risk of prolonged times to tracheal extubation with desflurane versus sevoflurane or isoflurane. Prolonged times are defined as ≥15 min from end of surgery (or anesthetic discontinuation) to extubation in the operating room. They are associated with reintubations, naloxone and flumazenil administration, longer times from procedure end to operating room exit, greater differences between actual and scheduled operating room times, longer times from operating room exit to next case start, longer durations of the workday, and more operating room personnel idle while waiting for extubation. Published randomized clinical trials of humans were included. Generalized pivotal methods were used to estimate the relative risk of prolonged extubation for each study from reported means and standard deviations of extubation times. The relative risks were combined using DerSimonian-Laird random effects meta-analysis with Knapp-Hartung adjustment. From 67 papers, there were 78 two-drug comparisons, including 5167 patients. Studies were of high quality (23/78) or moderate quality (55/78), the latter due to lack of blinding of observers to group assignment and/or patient attrition because patients were extubated after operating room exit. Desflurane resulted in a 65% relative reduction in the incidence of prolonged extubation compared with sevoflurane (95% confidence interval 49% to 76%, P < .0001) and in a 78% relative reduction compared with isoflurane (58% to 89%, P = .0001). There were no significant associations between studies' relative risks and quality, industry funding, or year of publication (all six meta-regressions P ≥ .35). In conclusion, when emergence from general anesthesia with different drugs are compared with sevoflurane or isoflurane, suitable benchmarks quantifying rapidity of emergence are reductions in the incidence of prolonged extubation achieved by desflurane, approximately 65% and 78%, respectively. These estimates give realistic context for interpretation of results of future studies that compare new anesthetic agents to current anesthetics.
Topics: Humans; Isoflurane; Sevoflurane; Desflurane; Risk; Airway Extubation; Anesthetics, Inhalation; Methyl Ethers; Anesthesia Recovery Period
PubMed: 37481911
DOI: 10.1016/j.jclinane.2023.111210 -
Frontiers in Pediatrics 2022The links of sedentary behavior and physical activity with health outcomes in children and adolescents is well known. However, the molecular mechanisms involved are...
BACKGROUND
The links of sedentary behavior and physical activity with health outcomes in children and adolescents is well known. However, the molecular mechanisms involved are poorly understood. We aimed to synthesize the current knowledge of the association of sedentary behavior and physical activity (acute and chronic effects) with gene expression and epigenetic modifications in children and adolescents.
METHODS
PubMed, Web of Science, and Scopus databases were systematically searched until April 2022. A total of 15 articles were eligible for this review. The risk of bias assessment was performed using the Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews and/or a modified version of the Downs and Black checklist.
RESULTS
Thirteen studies used candidate gene approach, while only 2 studies performed high-throughput analyses. The candidate genes significantly linked to sedentary behavior or physical activity were: , , -α, , , , and . Non-coding Ribonucleic acids (RNAs) regulated by sedentary behavior or physical activity were: miRNA-222, miRNA-146, miRNA-16, miRNA-126, miR-320, and long non-coding RNA MALAT1. These molecules are involved in inflammation, immune function, angiogenic process, and cardiovascular disease. Transcriptomics analyses detected thousands of genes that were altered following an acute bout of physical activity and are linked to gene pathways related to immune function, apoptosis, and metabolic diseases.
CONCLUSION
The evidence found to date is rather limited. Multidisciplinary studies are essential to characterize the molecular mechanisms in response to sedentary behavior and physical activity in the pediatric population. Larger cohorts and randomized controlled trials, in combination with multi-omics analyses, may provide the necessary data to bring the field forward.
SYSTEMATIC REVIEW REGISTRATION
[www.ClinicalTrials.gov], identifier [CRD42021235431].
PubMed: 35813370
DOI: 10.3389/fped.2022.917152 -
Medicine Sep 2016The differences in the incidence and severity of emergence agitation (EA) and emergence times between desflurane and sevoflurane anesthesia have not been as clearly... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
The differences in the incidence and severity of emergence agitation (EA) and emergence times between desflurane and sevoflurane anesthesia have not been as clearly elucidated in children as in adults.
METHODS
The design of the study is a systematic review with meta-analysis of randomized controlled trials. The study methodology is based on the Cochrane Review Methods. A comprehensive literature search was conducted to identify clinical trials comparing the incidence or severity of EA and emergence times in children anesthetized with desflurane or sevoflurane. Two reviewers independently assessed each study according to predefined inclusion criteria and extracted data from each study using a prespecified data extraction form. The data from each study were combined using a fixed effect or random effect model to calculate the pooled risk ratio (RR) or standardized mean difference (SMD) and 95% confidence interval (CI). Funnel plots were used to assess publication bias. Subgroup and sensitivity analyses were performed.
RESULTS
Fourteen studies met the inclusion criteria. Among the 1196 patients in these 14 studies, 588 received desflurane anesthesia and 608 received sevoflurane anesthesia. The incidence of EA was comparable between the 2 groups (pooled RR = 1.21; 95% CI: 0.96-1.53; I = 26%), and so was the severity of EA (EA score) between the 2 groups (SMD = 0.12; 95% CI: -0.02 to 0.27; I = 0%). Extubation and awakening times were shorter in the desflurane group than in the sevoflurane group; the weighted mean differences were -2.21 (95% CI: -3.62 to -0.81; I = 93%) and -2.74 (95% CI: -3.80 to -1.69; I = 85%), respectively. No publication bias was found in the funnel plot. The subgroup analysis based on the type of EA scale showed a higher incidence of EA in the desflurane group than in the sevoflurane group in studies using 3-, 4-, or 5-point EA scales; the pooled RR was 1.38 (95% CI: 1.10-1.73; I = 37%).
CONCLUSION
The incidence and severity of EA were comparable between desflurane and sevoflurane anesthesia in children; however, emergence times, including extubation and awakening times, were shorter in desflurane anesthesia.
Topics: Adolescent; Anesthesia, Inhalation; Anesthetics, Inhalation; Child; Child, Preschool; Desflurane; Emergence Delirium; Humans; Incidence; Isoflurane; Methyl Ethers; Sevoflurane; Time Factors
PubMed: 27661046
DOI: 10.1097/MD.0000000000004927 -
Genes Feb 2023Chronic pain represents a major global health issue in terms of psycho-physiological, therapeutic, and economic burden, not limited to adults but also to the pediatric... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
Chronic pain represents a major global health issue in terms of psycho-physiological, therapeutic, and economic burden, not limited to adults but also to the pediatric age. Despite its great impact, its molecular mechanisms have still not been completely unraveled. Focusing on the impact of epigenetics in the pain complex trait, we assessed the association between chronic pain and the methylation pattern of TRPA1, a key gene related to pain sensitivity.
METHODS
We conducted a systematic review retrieving articles from three different databases. After deduplication, 431 items were subjected to manual screening, and then 61 articles were selected and screened again. Of these, only six were maintained for meta-analysis and analyzed using specific R packages.
RESULTS
Six articles were divided into two groups (group 1: comparison of mean methylation levels between healthy subjects and patients with chronic pain; group 2: correlation between mean methylation levels and pain sensation). A non-significant mean difference was obtained from the analysis of group 1 with a value of 3.97 (95% C.I. -7.79; 15.73). Analysis of group 2 showed a high level of variability between studies (correlation = 0.35, 95% C.I. -0.12; 0.82) due to their heterogeneity (I = 97%, < 0.01).
CONCLUSIONS
Despite the high variability observed in the different studies analyzed, our results suggest that hypermethylation and increased pain sensitivity could be connected, possibly due to the variation of TRPA1 expression.
Topics: Adult; Child; Humans; Ankyrins; Chronic Pain; DNA Methylation; Epigenesis, Genetic; TRPA1 Cation Channel
PubMed: 36833338
DOI: 10.3390/genes14020411 -
Journal of Pharmacy & Pharmaceutical... 2022Till date, only systemic corticosteroids have demonstrated definite mortality benefit in management of COVID 19 in various studies. Still certain questions regarding the... (Meta-Analysis)
Meta-Analysis
PURPOSE
Till date, only systemic corticosteroids have demonstrated definite mortality benefit in management of COVID 19 in various studies. Still certain questions regarding the appropriate dose, duration and timing of corticosteroids remain unanswered. For this reason, the study was planned to determine the efficacy and safety of the pulse dose methyl prednisolone in management of COVID 19 from the publicly available evidence.
METHODS
PubMed, the Cochrane library, ClinicalTrials.gov and medRxiv were searched for articles reporting the use of pulse dose methyl prednisolone in COVID 19 from inception till 31st May, 2021. Odds ratios (ORs) were calculated for estimation of pooled effect by using random effect model and heterogeneity was checked by using I2 statistics.
RESULTS
Twelve studies (11 observational and 1 RCT) were included in the systematic review. A total of 3110 patients from 9 studies were included in the meta-analysis. Though the use of pulse dose methyl prednisolone demonstrated statistically significant mortality benefit in comparison to usual care (OR=0.71, 95% CI: 0.51 to 0.97, [P=0.03]), (I2= 21%) with calculated Number needed to treat (NNT) of 23.5, there was no statistically significant difference between the use of pulse dose and low dose corticosteroid (OR=0.66, 95% CI: 0.44 to 1.01, [(P=0.05]), (I2= 25%) and the NNT is 23.5. Incidence of adverse events were similar across all the groups. The grade of evidence for primary outcome was of moderate certainty.
CONCLUSION
This meta-analysis concurs with the previous reports regarding the use of corticosteroid in COVID 19 in comparison to usual care. However, for both the primary and secondary outcome, the study did not find any statistically significant difference between the use of pulse dose methyl prednisolone and low dose corticosteroid to treat COVID 19 patients.
Topics: Adrenal Cortex Hormones; Humans; Methylprednisolone; COVID-19 Drug Treatment
PubMed: 35364003
DOI: 10.18433/jpps32430 -
Schizophrenia Research Aug 2014N-methyl-d-aspartate receptor (NMDAR) antibodies have been documented in the serum of individuals with primary psychiatric disorders from several independent cohorts,... (Meta-Analysis)
Meta-Analysis Review
Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder.
BACKGROUND
N-methyl-d-aspartate receptor (NMDAR) antibodies have been documented in the serum of individuals with primary psychiatric disorders from several independent cohorts, but these findings have not been systematically assessed in aggregate or in relation to methodological covariates.
METHODS
We searched MEDLINE, EMBASE, and PsycINFO for studies in any language that provided data on NMDAR antibody seropositivity or absolute serum titers in schizophrenia or schizoaffective, bipolar, or major depressive disorders. We used a random effects model to pool estimates across studies.
RESULTS
Nine studies met the eligibility criteria. Five studies (3387 participants) provided data on NMDAR antibody seropositivity in psychiatric versus control groups based on high-specificity seropositivity thresholds (cell-based assays [CBAs]: 1:320 dilution, 1:200 dilution, visual score>1; enzyme-linked immunosorbent assay [ELISA]: 90(th) percentile of control titers). Meta-analysis showed significantly higher odds of NMDAR antibody seropositivity among those with schizophrenia or schizoaffective, bipolar, or major depressive disorders compared with healthy controls (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.04-9.27; P=.043; I(2)=68%). Four studies (3194 participants) provided outcome data for these groups based on low-specificity seropositivity thresholds (CBAs 1:10 dilution; ELISA: 75(th) percentile of control titers). Meta-analysis showed greater heterogeneity and no significant between-group difference (OR, 2.31; 95% CI, 0.55-9.73; P=.25; I(2)=90%). Seropositive participants in psychiatric groups had various combinations of IgG, IgM, and IgA class antibodies against NR1, NR1/NR2B, and NR2A/NR2B subunits. Subgroup analysis revealed significantly higher odds of seropositivity among all participants based on 1:10 versus 1:320 dilution seropositivity thresholds (OR, 4.56; 95% CI, 2.41-8.62; P<.001; I(2)=0%; studies=2, n=2920), but no apparent difference between first-episode and chronic schizophrenia or schizoaffective disorder (OR, 1.15; 95% CI, 0.19-7.24; P=.88, I(2)=43%, studies=2, n=1108). Average NR2A/NR2B antibody titers determined by ELISA were significantly higher among participants with first-episode schizophrenia (P<.0001) and acute mania (P<.01) compared with healthy controls. Levels decreased by 58% at 8weeks in first-episode schizophrenia, and by about 13% at 4days in acute mania.
CONCLUSIONS
Individuals with schizophrenia or schizoaffective, bipolar, or major depressive disorders are collectively about three times more likely to have elevated NMDAR antibody titers compared with healthy controls based on high-specificity, but not low-specificity, seropositivity thresholds, though considerable methodological and statistical heterogeneity exists. Evidence concerning the effect of disease state and time of serum acquisition is varied and consistent, respectively. Adequately powered longitudinal studies employing standardized assay methods and seropositivity threshold definitions, and quantifying NMDAR antibodies in both sera and cerebrospinal fluid are needed to further elucidate the clinical and pathophysiological implications of this association.
Topics: Autoantibodies; Bipolar Disorder; Depressive Disorder, Major; Humans; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 24882425
DOI: 10.1016/j.schres.2014.05.001 -
Cardiovascular Diabetology Mar 2019Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the efficacy and safety of pemafibrate, a novel selective peroxisome... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the efficacy and safety of pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia.
METHODS
A search was performed using the MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov databases. We decided to employ RCTs to evaluate the effects of pemafibrate on lipid and glucose metabolism-related parameters in patients with dyslipidemia. For statistical analysis, standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) were calculated using the random effect model.
RESULTS
Our search yielded seven RCTs (with a total of 1623 patients) that satisfied the eligibility criteria of this study; hence, those studies were incorporated into this meta-analysis. The triglyceride concentration significantly decreased in the pemafibrate group (SMD, - 1.38; 95% CI, - 1.63 to - 1.12; P < 0.001) than in the placebo group, with a reduction effect similar to that exhibited by fenofibrate. Compared with the placebo group, the pemafibrate group also showed improvements in high-density and non-high-density lipoprotein cholesterol levels as well as in homeostasis model assessment for insulin resistance. Furthermore, the pemafibrate group showed a significant decrease in hepatobiliary enzyme activity compared with the placebo and fenofibrate groups; and, total adverse events (AEs) were significantly lower in the pemafibrate group than in the fenofibrate group (OR, 0.60; 95% CI, 0.49-0.73; P < 0.001). In contrast, the low-density lipoprotein cholesterol level was significantly higher in the pemafibrate group than in the placebo (P = 0.006) and fenofibrate (P < 0.001) groups.
CONCLUSIONS
The lipid profile significantly improved in the pemafibrate group than in the placebo group. In addition to the pemafibrate group having an improved lipid profile, which was comparable with that of the fenofibrate group, the AEs were significantly lower than in the fenofibrate group and an improvement in hepatobiliary enzyme activity was also recognized. However, we believe that actual clinical data as well as long-term efficacy and safety need to be investigated in the future.
Topics: Benzoxazoles; Biliary Tract; Biomarkers; Butyrates; Dyslipidemias; Female; Humans; Hypolipidemic Agents; Lipids; Liver; Male; Middle Aged; PPAR alpha; Treatment Outcome
PubMed: 30898163
DOI: 10.1186/s12933-019-0845-x