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Clinical Microbiology and Infection :... Sep 2022The benefits of remdesivir in the treatment of hospitalized patients with COVID-19 remain debated with the National Institutes of Health and the World Health... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The benefits of remdesivir in the treatment of hospitalized patients with COVID-19 remain debated with the National Institutes of Health and the World Health Organization providing contradictory recommendations for and against use.
OBJECTIVES
To evaluate the role of remdesivir for hospitalized inpatients as a function of oxygen requirements.
DATA SOURCES
Beginning with our prior systematic review, we searched MEDLINE using PubMed from 15 January 2021 through 5 May 2022.
STUDY ELIGIBILITY CRITERIA
Randomised controlled trials; all languages.
PARTICIPANTS
All hospitalized adults with COVID-19.
INTERVENTIONS
Remdesivir, in comparison to either placebo, or standard of care.
ASSESSMENT OF RISK OF BIAS
We used the ROB-2 criteria.
METHODS OF DATA SYNTHESIS
The primary outcome was mortality, stratified by oxygen use (none, supplemental oxygen without mechanical ventilation, and mechanical ventilation). We conducted a frequentist random effects meta-analysis on the risk ratio scale and, to contextualize the probabilistic benefits, we also performed a Bayesian random effects meta-analysis on the risk difference scale. A ≥1% absolute risk reduction was considered clinically important.
RESULTS
We identified eight randomized trials, totaling 10 751 participants. The risk ratio for mortality comparing remdesivir vs. control was 0.77 (95% CI, 0.5-1.19) in the patients who did not require supplemental oxygen; 0.89 (95% CI, 0.79-0.99) for nonventilated patients requiring oxygen; and 1.08 (95% CI, 0.88-1.31) in the setting of mechanical ventilation. Using neutral priors, the probabilities that remdesivir reduces mortality were 76.8%, 93.8%, and 14.7%, respectively. The probability that remdesivir reduced mortality by ≥ 1% was 77.4% for nonventilated patients requiring oxygen.
CONCLUSIONS
Based on this meta-analysis, there is a high probability that remdesivir reduces mortality for nonventilated patients with COVID-19 requiring supplemental oxygen therapy. Treatment guidelines should be re-evaluated.
Topics: Adenosine Monophosphate; Adult; Alanine; Bayes Theorem; Humans; Oxygen; SARS-CoV-2; United States; COVID-19 Drug Treatment
PubMed: 35598856
DOI: 10.1016/j.cmi.2022.04.018 -
BMJ (Clinical Research Ed.) Jul 2020To compare the effects of treatments for coronavirus disease 2019 (covid-19). (Comparative Study)
Comparative Study
OBJECTIVE
To compare the effects of treatments for coronavirus disease 2019 (covid-19).
DESIGN
Living systematic review and network meta-analysis.
DATA SOURCES
WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 3 December 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 1 December 2021 were included in the analysis.
STUDY SELECTION
Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.
METHODS
After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.
RESULTS
463 trials enrolling 166 581 patients were included; 267 (57.7%) trials and 89 814 (53.9%) patients are new from the previous iteration; 265 (57.2%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, three drugs reduced mortality in patients with mostly severe disease with at least moderate certainty: systemic corticosteroids (risk difference 23 fewer per 1000 patients, 95% credible interval 40 fewer to 7 fewer, moderate certainty), interleukin-6 receptor antagonists when given with corticosteroids (23 fewer per 1000, 36 fewer to 7 fewer, moderate certainty), and Janus kinase inhibitors (44 fewer per 1000, 64 fewer to 20 fewer, high certainty). Compared with standard care, two drugs probably reduce hospital admission in patients with non-severe disease: nirmatrelvir/ritonavir (36 fewer per 1000, 41 fewer to 26 fewer, moderate certainty) and molnupiravir (19 fewer per 1000, 29 fewer to 5 fewer, moderate certainty). Remdesivir may reduce hospital admission (29 fewer per 1000, 40 fewer to 6 fewer, low certainty). Only molnupiravir had at least moderate quality evidence of a reduction in time to symptom resolution (3.3 days fewer, 4.8 fewer to 1.6 fewer, moderate certainty); several others showed a possible benefit. Several drugs may increase the risk of adverse effects leading to drug discontinuation; hydroxychloroquine probably increases the risk of mechanical ventilation (moderate certainty).
CONCLUSION
Corticosteroids, interleukin-6 receptor antagonists, and Janus kinase inhibitors probably reduce mortality and confer other important benefits in patients with severe covid-19. Molnupiravir and nirmatrelvir/ritonavir probably reduce admission to hospital in patients with non-severe covid-19.
SYSTEMATIC REVIEW REGISTRATION
This review was not registered. The protocol is publicly available in the supplementary material.
READERS' NOTE
This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fifth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Centers for Disease Control and Prevention, U.S.; China; Coronavirus Infections; Databases, Factual; Drug Combinations; Evidence-Based Medicine; Glucocorticoids; Humans; Hydroxychloroquine; Lopinavir; Network Meta-Analysis; Pandemics; Pneumonia, Viral; Randomized Controlled Trials as Topic; Respiration, Artificial; Ritonavir; SARS-CoV-2; Severity of Illness Index; Standard of Care; Treatment Outcome; United States; COVID-19 Drug Treatment
PubMed: 32732190
DOI: 10.1136/bmj.m2980 -
Advanced Drug Delivery Reviews Jan 2020Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main...
Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main driver for diversity of skin pigmentation. Dark melanin acts to protect against the deleterious effects of ultraviolet (UV) radiation, including photo-aging and skin cancer formation. In turn, UV radiation activates skin melanocytes to induce further pigmentation (i.e., "tanning pathway"). The well-characterized MSH/MC1R-cAMP-MITF pathway regulates UV-induced melanization. Pharmacologic activation of this pathway ("sunless tanning") represents a potential strategy for skin cancer prevention, particularly in those with light skin or the "red hair" phenotype who tan poorly after UV exposure due to MC1R inactivating polymorphisms. Skin hyperpigmentation can also occur as a result of inflammatory processes and dermatological disorders such as melasma. While primarily of cosmetic concern, these conditions can dramatically impact quality of life of affected patients. Several topical agents are utilized to treat skin pigmentation disorders. Here, we review melanogenesis induced by UV exposure and the agents that target this pathway.
Topics: Administration, Cutaneous; Cyclic AMP; Dermatologic Agents; Drug Delivery Systems; Humans; Melanins; Pigmentation Disorders; Protein Kinases; Skin Pigmentation; Ultraviolet Rays
PubMed: 32092380
DOI: 10.1016/j.addr.2020.02.002 -
Frontiers in Public Health 2022Evidence is scarce about the effect of noise exposure on the risk of dementia. We conducted a systematic review and dose-response meta-analysis, aiming to explore the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Evidence is scarce about the effect of noise exposure on the risk of dementia. We conducted a systematic review and dose-response meta-analysis, aiming to explore the association between noise exposure and the risk of dementia.
METHODS
We searched PubMed, EMBASE and the Cochrane Library to collect studies on chronic noise exposure and the risk of dementia from database inception to September 18, 2021 without language limitations. Two authors independently screened the literature, extracted data and assessed the risk of bias of the included studies. A dose-response meta-analysis and subgroup analysis were then conducted to detect the association between noise exposure and the risk of dementia by using Stata 14.0 software. This study is registered on PROSPERO (CRD42021249243).
RESULTS
A total of 11 studies were eligible for qualitative synthesis, and nine were eligible for quantitative data synthesis. All of them showed moderate to high quality scores in the assessment of risk of bias. We found a positive linear association between the noise increment and dementia risk ( = 0.58). When noise exposure increased 57 dB, the RR of dementia was 1.47 (95% CI: 1.21-1.78). From the outcome subgroup of AD, AD and dementia, VaD and NAD, we also found a positive association ( = 0.68, 0.68, 0.58, respectively). When noise exposure increased by 25 dB, the RRs were 1.18 (95% CI: 1.14-1.23), 1.19 (95% CI: 1.14-1.23) and 1.17 (95% CI: 1.06-1.30), respectively. We found a nonlinear association between the noise increment and dementia risk when only cohort studies were included ( = 0.58). When noise exposure increased by 25 dB, the RR of dementia was 1.16 (95% CI: 1.12-1.20). From the subgroup of AD, AD and dementia, VaD and NAD of cohort studies, the regression curve showed a nonlinear positive association ( = 0.74, 0.71, 0.43, respectively). When noise exposure increased by 25 dB, the RRs were 1.17 (95% CI: 1.12-1.21), 1.17 (95% CI: 1.12-1.22) and 1.13 (95% CI: 0.99-1.28), respectively.
CONCLUSION
Based on the current evidence, exposure to noise may be a specific risk factor for dementia. To better prevent dementia, more rigorously designed studies are needed to explore the etiological mechanism of noise and dementia.
Topics: Cohort Studies; Databases, Factual; Dementia; Humans; NAD; Risk Factors
PubMed: 35795699
DOI: 10.3389/fpubh.2022.832881 -
International Journal of Molecular... Apr 2023The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global health concern. Three years... (Review)
Review
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global health concern. Three years since its origin, despite the approval of vaccines and specific treatments against this new coronavirus, there are still high rates of infection, hospitalization, and mortality in some countries. COVID-19 is characterised by a high inflammatory state and coagulation disturbances that may be linked to purinergic signalling molecules such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine (ADO), and purinergic receptors (P1 and P2). These nucleotides/nucleosides play important roles in cellular processes, such as immunomodulation, blood clot formation, and vasodilation, which are affected during SARS-CoV-2 infection. Therefore, drugs targeting this purinergic pathway, currently used for other pathologies, are being evaluated in preclinical and clinical trials for COVID-19. In this review, we focus on the potential of these drugs to control the release, degradation, and reuptake of these extracellular nucleotides and nucleosides to treat COVID-19. Drugs targeting the P1 receptors could have therapeutic efficacy due to their capacity to modulate the cytokine storm and the immune response. Those acting in P2X7, which is linked to NLRP3 inflammasome activation, are also valuable candidates as they can reduce the release of pro-inflammatory cytokines. However, according to the available preclinical and clinical data, the most promising medications to be used for COVID-19 treatment are those that modulate platelets behaviour and blood coagulation factors, mainly through the P2Y12 receptor.
Topics: Humans; Nucleosides; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Adenosine Triphosphate; Adenosine Diphosphate; Receptors, Purinergic
PubMed: 37175571
DOI: 10.3390/ijms24097865 -
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 -
European Review For Medical and... Sep 2020In December 2019, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection broke out in Wuhan, China. However, we still lack a comprehensive understanding...
OBJECTIVE
In December 2019, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection broke out in Wuhan, China. However, we still lack a comprehensive understanding of this emerging virus. In this manuscript, we collected relevant articles and reviewed the characteristics about SARS-CoV-2.
MATERIALS AND METHODS
We performed an online search on PubMed and Web of Science with the keywords COVID-19, 2019-nCoV and SARS-CoV-2, and summarized the epidemiology, virology, clinical features and treatments of SARS-CoV-2 infection.
RESULTS
We retrieved 157 published papers about SARS-CoV-2 from January, 2020 to April, 2020. We found that SARS-CoV-2 was a kind of virus with low mortality rate and high infectivity. This virus can enter human cells through angiotensin-converting enzyme 2 (ACE2) in alveoli and activate immune response in human body. SARS-CoV-2 infection can be classified as asymptomatic, mild, common, severe, and critical. We summarized antiviral drugs against SARS-CoV-2, such as remdesivir, hydroxychloroquine and favipiravir. Because the vaccine of SARS-CoV-2 is developing, more clinical studies are needed to verify the safety and efficacy of these treatments.
CONCLUSIONS
SARS-CoV-2 is a novel coronavirus that has caused a global pandemic. We should pay more attention to prevent SARS-CoV-2 and try to control it sooner.
Topics: Adenosine Monophosphate; Alanine; Angiotensin-Converting Enzyme 2; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Extracorporeal Membrane Oxygenation; Glucocorticoids; Humans; Immunization, Passive; Immunotherapy; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; SARS-CoV-2
PubMed: 32965016
DOI: 10.26355/eurrev_202009_22873 -
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 -
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