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Journal of Alzheimer's Disease : JAD 2022The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent.
OBJECTIVE
To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC).
METHODS
Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models.
RESULTS
Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy.
CONCLUSION
Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD.
Topics: Alzheimer Disease; Autophagy; Biomarkers; Endosomes; Humans; Lysosomes; NAD
PubMed: 35754279
DOI: 10.3233/JAD-220360 -
Advances in Therapy Dec 2023Clofarabine monotherapy at a dose of 52 mg/m per day was approved in the USA in 2004 for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL)... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Clofarabine monotherapy at a dose of 52 mg/m per day was approved in the USA in 2004 for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL) in patients aged 1-21 years after at least two prior regimens. To address a post-marketing requirement for additional evidence of the clinical benefit of clofarabine in its approved indication, a meta-analysis of patient-level data was conducted.
METHODS
A systematic literature review was conducted, using the Dr.Evidence software platform, DOC Search, and Embase, to identify clinical trials with patients with R/R ALL who received clofarabine monotherapy at 52 mg/m. The primary endpoint was complete remission (CR). Secondary endpoints were overall remission (OR, defined by CR or CR with either incomplete platelet recovery or incomplete neutrophil and platelet recovery), duration of response, overall survival (OS), and safety.
RESULTS
A total of 754 patients in 12 clinical studies were analyzed including 682 patients with R/R ALL treated with clofarabine monotherapy at 52 mg/m; of them, 374 were aged < 22 years (pediatric population). Rates of CR and OR were 16% (95% confidence interval [CI] 7, 26) and 28% (95% CI 20, 37), respectively, in the pediatric population and 12% (95% CI 5, 21) and 21% (95% CI 13, 31) in the overall population. Median OS (evaluable in three studies in pediatric patients) was 3.7 months (95% CI 0.1, 31.4), reaching 10.1 months (95% CI 0.3, 68.9) for those achieving OR. Sensitivity analyses supported these findings. The most frequent grade 3-4 adverse events were liver abnormalities, anemia, diarrhea, and febrile neutropenia.
CONCLUSION
In this meta-analysis, CR duration and median OS in pediatric patients with R/R ALL appeared to be slightly longer than in the phase II study. No new safety signals were identified. Results support the use of clofarabine monotherapy in its approved indication.
Topics: Child; Humans; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Clofarabine; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Clinical Trials as Topic
PubMed: 37819554
DOI: 10.1007/s12325-023-02696-7 -
Frontiers in Immunology 2022Tryptophan (TRP) is an essential amino acid that must be provided in the diet. The kynurenine pathway (KP) is the main route of TRP catabolism into nicotinamide... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tryptophan (TRP) is an essential amino acid that must be provided in the diet. The kynurenine pathway (KP) is the main route of TRP catabolism into nicotinamide adenosine dinucleotide (NAD), and metabolites of this pathway may have protective or degenerative effects on the nervous system. Thus, the KP may be involved in neurodegenerative diseases.
OBJECTIVES
The purpose of this systematic review and meta-analysis is to assess the changes in KP metabolites such as TRP, kynurenine (KYN), kynurenic acid (KYNA), Anthranilic acid (AA), 3-hydroxykynurenine (3-HK), 5-Hydroxyindoleacetic acid (5-HIAA), and 3-Hydroxyanthranilic acid (3-HANA) in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) patients compared to the control group.
METHODS
We conducted a literature search using PubMed/Medline, Scopus, Google Scholar, Web of Science, and EMBASE electronic databases to find articles published up to 2022. Studies measuring TRP, KYN, KYNA, AA, 3-HK, 5-HIAA, 3-HANA in AD, PD, or HD patients and controls were identified. Standardized mean differences (SMDs) were used to determine the differences in the levels of the KP metabolites between the two groups.
RESULTS
A total of 30 studies compromising 689 patients and 774 controls were included in our meta-analysis. Our results showed that the blood levels of TRP was significantly lower in the AD (SMD=-0.68, 95% CI=-0.97 to -0.40, p=0.000, I2 = 41.8%, k=8, n=382), PD (SMD=-0.77, 95% CI=-1.24 to -0.30, p=0.001, I2 = 74.9%, k=4, n=352), and HD (SMD=-0.90, 95% CI=-1.71 to -0.10, p=0.028, I2 = 91.0%, k=5, n=369) patients compared to the controls. Moreover, the CSF levels of 3-HK in AD patients (p=0.020) and the blood levels of KYN in HD patients (p=0.020) were lower compared with controls.
CONCLUSION
Overall, the findings of this meta-analysis support the hypothesis that the alterations in the KP may be involved in the pathogenesis of AD, PD, and HD. However, additional research is needed to show whether other KP metabolites also vary in AD, PD, and HD patients. So, the metabolites of KP can be used for better diagnosing these diseases.
Topics: Humans; Kynurenine; Kynurenic Acid; Tryptophan; Hydroxyindoleacetic Acid; Alzheimer Disease; Parkinson Disease; Huntington Disease; 3-Hydroxyanthranilic Acid; NAD; Adenosine; Niacinamide
PubMed: 36263032
DOI: 10.3389/fimmu.2022.997240 -
American Journal of Cardiovascular... Jan 2024Cangrelor is a potent intravenous non-thienopyridine P2Y12 inhibitor. We conducted a network meta-analysis to study the efficacy and safety of cangrelor as compared with... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Cangrelor is a potent intravenous non-thienopyridine P2Y12 inhibitor. We conducted a network meta-analysis to study the efficacy and safety of cangrelor as compared with the oral P2Y12 inhibition, clopidogrel, or placebo in acute coronary syndromes.
METHODS
This meta-analysis followed the Cochrane collaboration guidelines and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols. Outcomes of interest included all-cause mortality, myocardial infarction, stent thrombosis, target vessel revascularization, major bleeding, minor bleeding, and the need for blood transfusion.
RESULTS
The analysis was comprised of 6 studies including 26,444 patients treated with cangrelor, clopidogrel, or placebo. There were no statistically significant differences in the incidence of all-cause mortality, myocardial infarction, stent thrombosis, target vessel revascularization, or major bleeding. Cangrelor was associated with a higher risk of minor bleeding than clopidogrel or placebo, with no difference in requiring blood transfusion.
CONCLUSION
Cangrelor has comparable outcomes to clopidogrel in patients with acute coronary syndromes and can be used as a reliable alternative in this population.
Topics: Humans; Clopidogrel; Acute Coronary Syndrome; Platelet Aggregation Inhibitors; Network Meta-Analysis; Purinergic P2Y Receptor Antagonists; Adenosine Monophosphate; Myocardial Infarction; Hemorrhage; Percutaneous Coronary Intervention; Treatment Outcome; Thrombosis
PubMed: 37995040
DOI: 10.1007/s40256-023-00616-2 -
Infection Feb 2022This review was aimed to synthesise the best available evidence on the effectiveness and safety of remdesivir in the treatment of moderate to severe COVID-19. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
This review was aimed to synthesise the best available evidence on the effectiveness and safety of remdesivir in the treatment of moderate to severe COVID-19.
METHOD
Randomised controlled trials (RCTs) and observational studies reporting the effectiveness and safety of remdesivir were searched via databases and other sources from December 2019 to December 2020. Two independent reviewers performed literature screening, data extraction and assessment of risk bias. Seven studies involving 3686 patients were included.
RESULTS
Treatment with remdesivir was associated with an increase in clinical recovery rate by 21% (RR 1.21; 95% CI 1.08-1.35) on day 7 and 29% (RR 1.29; 95% CI 1.22-1.37) on day 14. The likelihoods of requiring high-flow supplemental oxygen and invasive mechanical ventilation in the remdesivir group were lower than in the placebo group by 27% (RR 0.73; 95% CI 0.54-0.99) and 47% (RR 0.53; 95% CI 0.39-0.72), respectively. Remdesivir-treated patients showed a 39% (RR 0.61; 95% CI 0.46-0.79) reduction in the risk of mortality on day 14 compared to the control group; however, there was no significant difference on day 28. Serious adverse effects (SAEs) were significantly less common in patients treated with remdesivir, with an absolute risk difference of 6% (RD -0.06; 95% CI -0.09 to -0.03).
CONCLUSION
Despite conditional recommendation against its use, remdesivir could still be effective in early clinical improvement; reduction of early mortality and avoiding high-flow supplemental oxygen and invasive mechanical ventilation among hospitalised COVID-19 patients. Remdesivir was also well tolerated without significant SAEs compared to placebo, yet available evidence from clinical studies support the need to conduct close monitoring.
Topics: Adenosine Monophosphate; Alanine; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34331674
DOI: 10.1007/s15010-021-01671-0 -
Frontiers in Endocrinology 2022Novel atherogenic lipid indices, including non-high-density lipoprotein cholesterol (non-HDL-C) which is calculated by subtracting the HDL-C value from the total... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Novel atherogenic lipid indices, including non-high-density lipoprotein cholesterol (non-HDL-C) which is calculated by subtracting the HDL-C value from the total cholesterol level, atherogenic index (ratio between triglycerides (TG) and HDL-C concentrations (TG/HDL-C)), and Diff-C (calculated by subtracting low-density lipoprotein (LDL-C) from non-HDL-C), have been known as valuable predictors of dyslipidemia and subsequent cardiovascular diseases. Previous studies have reported the potential association of novel atherogenic lipid indices with metabolic syndrome (MetS). This meta-analysis aimed to assess the pooled association of novel atherogenic lipid indices with MetS or its components.
METHODS
A systematic search was conducted through PubMed, Scopus, and Web of Science (WoS) databases from January 2000 until March 2021 to evaluate the association of novel atherogenic lipid indices, including non-HDL-C, atherogenic index, and the difference between non-HDL-C and LDL-C (Diff-C) with MetS. Observational studies were included without any language restriction. As exclusive studies evaluating the association of non-HDL-C with metabolic syndrome (MetS) were eligible to be included in quantitative analyses, a random-effect meta-analysis was performed to pool the odds ratios (ORs). A stratified meta-analysis was performed based on the definition of MetS [Adult Treatment Panel (ATP) and International Diabetes Federation (IDF)] and the studied population.
RESULTS
Overall, 318 studies were retrieved from an initial systematic search. After screening, 18 and five studies were included in the qualitative and quantitative syntheses, respectively. Qualitative synthesis revealed an association between non-HDL-C, Diff-C, and atherogenic index with MetS and its components. Stratified meta-analysis showed that an increased non-HDL-C level was associated with an increased odds of MetS based on ATP criteria (OR: 3.77, 95% CI: 2.14-5.39) and IDF criteria (OR: 2.71, 95% CI: 1.98-3.44) in adults (OR: 3.53, 95% CI: 2.29-4.78) and in children (OR: 2.27, 95% CI: 1.65-2.90).
CONCLUSION
Novel atherogenic lipid indices, including atherogenic index, Diff-c, and non-HDL-C, are strongly associated with increased odds of MetS and its components. The indices could be considered as potential predictors of MetS and its components in clinical practice.
Topics: Adenosine Triphosphate; Adult; Child; Cholesterol; Cholesterol, LDL; Diabetes Mellitus; Humans; Metabolic Syndrome; Triglycerides
PubMed: 36176470
DOI: 10.3389/fendo.2022.957136 -
Evaluation of safety and effectiveness of NAD in different clinical conditions: a systematic review.American Journal of Physiology.... Apr 2024Nicotinamide adenine dinucleotide (NAD) is an essential pyridine nucleotide cofactor that is present in cells and in several important biological processes, including... (Review)
Review
Nicotinamide adenine dinucleotide (NAD) is an essential pyridine nucleotide cofactor that is present in cells and in several important biological processes, including oxidative phosphorylation and production of adenosine triphosphate, DNA repair, calcium-dependent secondary messenger and gene expression. The purpose of this systematic review is to examine whether the coenzyme formulae NAD and NADH are safe and effective when acting as a supplement to humans. This systematic review of randomized clinical trials performed a search in six electronic databases: PubMed, MEDLINE (), Embase, Cochrane CENTRAL (clinical trials), Web of Science, and Scopus. Secondary search included the databases (e.g., Clinical trials.gov, Rebec, Google Scholar - advance). Two reviewers assessed and extracted the studies independently. The risk of bias in studies was performed using version 2 of the Cochrane risk of bias tool for randomized trials. This review includes 10 studies, with a total of 489 participants. The studies included different clinical conditions, such as chronic fatigue syndrome (CFS), older adults, Parkinson's disease, overweight, postmenopausal prediabetes, and Alzheimer's disease. Based on studies, the supplementation with NADH and precursors was well tolerated and observed clinical results such as, a decrease in anxiety conditions and maximum heart rate was observed after a stress test, increased muscle insulin sensitivity, insulin signaling. Quality of life, fatigue intensity, and sleep quality among others were evaluated on patients with CFS. All studies showed some side effects, thus, the most common associated with NADs use are muscle pain, nervous disorders, fatigue, sleep disturbance, and headaches. All adverse events cataloged by the studies did not present a serious risk to the health of the participants. Overall, these findings support that the oral administration of NADH can be associated to an increase in general quality of life and improvement on health parameters (e.g., a decrease in anxiety, maximum heart rate, inflammatory cytokines in serum, and cerebrospinal fluid). NADH supplementation is safe and has a low incidence of side effects. Future investigations are needed to evidence the clinical benefits regarding specific diseases and doses administered.
Topics: Humans; Aged; Quality of Life; Fatigue Syndrome, Chronic; NAD; Dietary Supplements
PubMed: 37971292
DOI: 10.1152/ajpendo.00242.2023 -
Jornal Brasileiro de Pneumologia :... 2022Studies in the literature regarding the use of remdesivir to treat COVID-19 patients have shown conflicting results. This study sought to answer questions related to the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Studies in the literature regarding the use of remdesivir to treat COVID-19 patients have shown conflicting results. This study sought to answer questions related to the use of remdesivir for the treatment of patients hospitalized with moderate to severe COVID-19.
METHODS
This was a systematic review and meta-analysis including phase 3 randomized clinical trials (RCTs) and observational cohort studies selected from various databases, comparing patients hospitalized with moderate to severe COVID-19 receiving remdesivir and controls.
RESULTS
A total of 207 studies were retrieved, 9 of which met the eligibility criteria and were included in the study. The meta-analysis using RCTs alone showed no statistically significant differences regarding mortality or use of mechanical ventilation/extracorporeal membrane oxygenation between remdesivir and control groups, and the quality of evidence was moderate and low, respectively. The use of remdesivir increased the recovery rate by 6% (95% CI, 3-9); p = 0.004) and the clinical improvement rate by 7% (95% CI, 1-14); p = 0.02). Additionally, no significant differences in mortality were found between remdesivir and control groups when the meta-analysis used observational cohort studies alone (risk difference = -0.01 (95% CI, -0.02 to 0.01; p = 0.32), the quality of evidence being moderate, and the risk of adverse events was 4% ([95% CI, -0.08 to 0.01]; p = 0.09).
CONCLUSIONS
The use of remdesivir for the treatment of patients with moderate to severe COVID-19 had no significant impact on clinically important outcomes.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Humans; Observational Studies as Topic; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 35137874
DOI: 10.36416/1806-3756/e20210393 -
BJU International Dec 2023To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic... (Meta-Analysis)
Meta-Analysis Review
Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis.
OBJECTIVES
To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving a combination of first-line poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARAT) vs placebo/ARAT.
MATERIALS AND METHODS
We conducted a systematic review/meta-analysis of all published Phase III randomised controlled trials using EMBASE, MEDLINE, and Cochrane (inception until 6 June 2023). Published full-text manuscripts and conference abstracts were inclusion eligible. Study selection/data extraction were independently performed by two authors. The Cochrane Risk-of-Bias 2 Tool was used, and certainty of evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Pooled hazard ratios (HRs) and relative risks, with corresponding confidence intervals (CIs), were generated using random-effects models.
RESULTS
Three trials were identified: PROpel, MAGNITUDE, and TALAPRO-2. Compared to placebo/ARAT, the PARPi/ARAT combination was associated with a 35% rPFS improvement in the overall cohort (HR 0.65, 95% CI 0.56-0.76), with 68%, 45%, and 26% improvements in the BReast CAncer gene 1/gene 2 (BRCA1/2)-mutated (BRCA1/2m; P < 0.001), homologous recombination repair-mutated (HRRm; P < 0.001), and non-HRRm cohorts (P = 0.003), respectively. OS data maturity ranged from 31% to 48%, with overall cohort OS data unavailable from MAGNITUDE. The PROpel/TALAPRO-2 pooled analysis demonstrated a 16% OS improvement in the overall cohort (HR 0.84, 95 CI 0.72-0.98; P = 0.02). OS in the HRRm (HR 0.76, 95% CI 0.61-0.95) and the BRCA1/2m cohorts (HR 0.53, 95% CI 0.18-1.56) were improved, with a higher effect magnitude compared to the overall cohort. This combination was associated with a 45% relative risk increase in Grade ≥3 TEAEs, including 6.22-fold for Grade ≥3 anaemia (31.9% vs 4.9%).
CONCLUSIONS
The addition of PARPi to ARAT in the first-line mCRPC setting is associated with rPFS benefits across subgroups, with the greatest magnitude of benefit in BRCA1/2m patients. OS benefits remain inconsistent irrespective of HRRm status, with significant increases in Grade ≥3 TEAEs, particularly anaemia. Currently, we suggest this combined approach be selectively offered to HRRm patients, preferentially BRCA1/2m.
Topics: Male; Humans; BRCA1 Protein; Ribose; Prostatic Neoplasms, Castration-Resistant; BRCA2 Protein; Anemia; Adenosine Diphosphate
PubMed: 37461140
DOI: 10.1111/bju.16130 -
ACS Biomaterials Science & Engineering May 2022Biomaterial-associated infection is difficult to detect and brings consequences that can lead to morbidity and mortality. Bacteria can adhere to the implant surface,... (Meta-Analysis)
Meta-Analysis Review
Biomaterial-associated infection is difficult to detect and brings consequences that can lead to morbidity and mortality. Bacteria can adhere to the implant surface, grow, and form biofilms. Antimicrobial peptides (AMPs) can target and kill bacterial cells using a plethora of mechanisms of action such as rupturing the cell membrane by creating pores via depolarization with their cationic and amphipathic nature. AMPs can thus be coated onto metal implants to prevent microbial cell adhesion and growth. The aim of this systematic review was to determine the potential clinical applications of AMP-modified implants through in vivo induced infection models. Following a database search recently up to 22 January 2022 using PubMed, Web of Science and Cochrane databases, and abstract/title screening using the PRISMA framework, 24 studies remained, of which 18 were used in the random effects meta-analysis of standardized mean differences (SMD) to get effect sizes. Quality of studies was assessed using SYRCLE's risk of bias tool. The data from these 18 studies showed that AMPs carry antibacterial effects, and the meta-analysis confirmed the favorited antibacterial efficacy of AMP-coated groups over controls (SMD -1.74, 95%CI [-2.26, -1.26], < 0.00001). Subgroup analysis showed that the differences in effect size are random, and high heterogeneity values suggested the same. HHC36 and vancomycin were the most common AMPs for surface modification and , the most tested bacterium in vivo. Covalent binding with polymer brush coating and physical layer-by-layer incorporation of AMPs were recognized as key methods of incorporation to achieve desired densities. The use of fusion peptides seemed admirable to incorporate additional benefits such as osteointegration and wound healing and possibly targeting more microbe strains. Further investigation into the incorporation methods, AMP activity against different bacterial strains, and the number of AMPs used for metal implant surface modification is needed to progress toward potential clinical application.
Topics: Adenosine Monophosphate; Anti-Bacterial Agents; Antimicrobial Peptides; Bacteria; Biofilms; Staphylococcus aureus
PubMed: 35412810
DOI: 10.1021/acsbiomaterials.1c01307