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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 -
Experimental Gerontology Apr 2020Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that is present in all living cells. NAD+ acts as an important cofactor and substrate for a...
Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that is present in all living cells. NAD+ acts as an important cofactor and substrate for a multitude of biological processes including energy production, DNA repair, gene expression, calcium-dependent secondary messenger signalling and immunoregulatory roles. The de novo synthesis of NAD+ is primarily dependent on the kynurenine pathway (KP), although NAD+ can also be recycled from nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NAD+ levels have been reported to decline during ageing and age-related diseases. Recent studies have shown that raising intracellular NAD+ levels represents a promising therapeutic strategy for age-associated degenerative diseases in general and to extend lifespan in small animal models. A systematic review of the literature available on Medline, Embase and Pubmed was undertaken to evaluate the potential health and/or longevity benefits due to increasing NAD+ levels. A total of 1545 articles were identified and 147 articles (113 preclinical and 34 clinical) met criteria for inclusion. Most studies indicated that the NAD+ precursors NAM, NR, nicotinamide mononucleotide (NMN), and to a lesser extent NAD+ and NADH had a favourable outcome on several age-related disorders associated with the accumulation of chronic oxidative stress, inflammation and impaired mitochondrial function. While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials.
Topics: Aging; Animals; Humans; Inflammation; Mice; NAD; Neurodegenerative Diseases; Niacinamide; Nicotinamide Mononucleotide; Oxidative Stress; Pyridinium Compounds; Rats; Risk Assessment
PubMed: 31917996
DOI: 10.1016/j.exger.2020.110831 -
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 -
Journal of Clinical Oncology : Official... Sep 2022To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline.
PURPOSE
To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline.
METHODS
An Expert Panel conducted a systematic review to identify randomized clinical trials and prospective-retrospective studies from January 2015 to January 2022.
RESULTS
The search identified 19 studies informing the evidence base.
RECOMMENDATIONS
Candidates for a regimen with a phosphatidylinositol 3-kinase inhibitor and hormonal therapy should undergo testing for mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine eligibility for alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used. Patients who are candidates for poly (ADP-ribose) polymerase (PARP) inhibitor therapy should undergo testing for germline and pathogenic or likely pathogenic mutations to determine eligibility for a PARP inhibitor. There is insufficient evidence for or against testing for a germline pathogenic variant to determine eligibility for PARP inhibitor therapy in the metastatic setting. Candidates for immune checkpoint inhibitor therapy should undergo testing for expression of programmed cell death ligand-1 in the tumor and immune cells to determine eligibility for treatment with pembrolizumab plus chemotherapy. Candidates for an immune checkpoint inhibitor should also undergo testing for deficient mismatch repair/microsatellite instability-high to determine eligibility for dostarlimab-gxly or pembrolizumab, as well as testing for tumor mutational burden. Clinicians may test for fusions to determine eligibility for TRK inhibitors. There are insufficient data to recommend routine testing of tumors for mutations, for homologous recombination deficiency, or for TROP2 expression to guide MBC therapy selection. There are insufficient data to recommend routine use of ctDNA or circulating tumor cells to monitor response to therapy among patients with MBC.Additional information can be found at www.asco.org/breast-cancer-guidelines.
Topics: Adenosine Diphosphate; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Breast Neoplasms; Circulating Tumor DNA; Class I Phosphatidylinositol 3-Kinases; Female; Fulvestrant; Humans; Immune Checkpoint Inhibitors; Ligands; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerase Inhibitors; Prospective Studies; Retrospective Studies; Ribose
PubMed: 35759724
DOI: 10.1200/JCO.22.01063 -
Neuroscience and Biobehavioral Reviews Dec 2023Non-Alzheimer's dementia (NAD) accounts for 30% of all neurodegenerative conditions and is characterized by cognitive decline beyond mere memory dysfunction. Diagnosing... (Meta-Analysis)
Meta-Analysis Review
Non-Alzheimer's dementia (NAD) accounts for 30% of all neurodegenerative conditions and is characterized by cognitive decline beyond mere memory dysfunction. Diagnosing NAD remains challenging due to the lack of established biomarkers. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with NAD and healthy controls. Our meta-analyses indicated that TMS neurophysiological examinations revealed decreased glutamatergic function in patients with frontotemporal dementia (FTD) and decreased GABAergic function in patients with FTD, progressive supranuclear palsy, Huntington's disease, cortico-basal syndrome, and multiple system atrophy-parkinsonian type. In addition, decreased cholinergic function was found in dementia with Lewy body and vascular dementia. These results suggest the potential of TMS as an additional diagnostic tool to differentiate NAD.
Topics: Humans; Transcranial Magnetic Stimulation; Frontotemporal Dementia; Neurodegenerative Diseases; NAD; Alzheimer Disease; Cholinergic Agents; Neural Inhibition; Evoked Potentials, Motor
PubMed: 37926239
DOI: 10.1016/j.neubiorev.2023.105451 -
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 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 -
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 -
European Journal of Clinical... Nov 2020Several therapeutic agents have been investigated for treatment of novel coronavirus 2019 (nCOV-2019). We conducted a systematic review and meta-analysis to assess the... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Several therapeutic agents have been investigated for treatment of novel coronavirus 2019 (nCOV-2019). We conducted a systematic review and meta-analysis to assess the efficacy of various treatment modalities in nCOV-2019 patients.
METHODS
A literature search was conducted before 29 June 2020 in PubMed, Google Scholar and Cochrane library databases. A fixed-effect model was applied if I < 50%, else results were combined using random-effect model. Risk ratio (RR) or standardized mean difference (SMD) along with 95% confidence interval (95% CI) was used to pool the results. Between-study heterogeneity was explored using influence and sensitivity analyses, and publication bias was assessed using funnel plots. Entire statistical analysis was conducted in R version 3.6.2.
RESULTS
Fifty studies involving 15 in vitro and 35 clinical studies including 9170 nCOV-2019 patients were included. Lopinavir-ritonavir was significantly associated with shorter mean time to clinical recovery (SMD -0.32; 95% CI -0.57 to -0.06), remdesivir was significantly associated with better overall clinical recovery (RR 1.17; 95% CI 1.07 to 1.29), and tocilizumab was associated with less all-cause mortality (RR 0.38; 95% CI 0.16 to 0.93). Hydroxychloroquine was associated with longer time to clinical recovery and less overall clinical recovery. It additionally had higher all-cause mortality and more total adverse events.
CONCLUSION
Our meta-analysis suggests that except in vitro studies, no treatment has shown overall favourable outcomes in nCOV-2019 patients. Lopinavir-ritonavir, remdesivir and tocilizumab may have some benefits, while hydroxychloroquine administration may cause harm in nCOV-2019 patients. Results from upcoming large clinical trials may further clarify role of these drugs.
Topics: Adenosine Monophosphate; Alanine; Antibodies, Monoclonal, Humanized; Antiviral Agents; COVID-19; Coronavirus Infections; Europe; Female; Humans; Lopinavir; Male; Pandemics; Pneumonia, Viral; Prognosis; Ritonavir; Survival Analysis; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32810285
DOI: 10.1111/eci.13383