Concentrations, Number of Doses, and Formulations of Aluminium Adjuvants in Vaccines: A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials.

Aluminium adjuvants are commonly used in vaccines to boost the effects of vaccination. Here, we assessed the benefits and harms of different aluminium adjuvants vs. other aluminium adjuvants or vs. the same aluminium adjuvant at other concentrations, administered a different number of doses, or at different particle sizes used in vaccines or vaccine excipients. We conducted a systematic review with meta-analysis and Trial Sequential Analysis to assess the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We obtained data from major medical databases until 20 January 2023 and included 10 randomized clinical trials of healthy volunteers. The comparisons assessed higher vs. lower aluminium adjuvant concentrations; higher vs. lower number of doses of aluminium adjuvant; and aluminium phosphate adjuvant vs. aluminium hydroxide adjuvant. For all three comparisons, meta-analyses showed no evidence of a difference on all-cause mortality, serious adverse events, and adverse events considered non-serious. The certainty of evidence was low to very low. None of the included trials reported on quality of life or proportion of participants who developed the disease being vaccinated against. The benefits and harms of different types of aluminium adjuvants, different aluminium concentrations, different number of doses, or different particle sizes, therefore, remain uncertain.

Aluminium adjuvants versus placebo or no intervention in vaccine randomised clinical trials: a systematic review with meta-analysis and Trial Sequential Analysis.

OBJECTIVES: To assess the benefits and harms of aluminium adjuvants versus placebo or no intervention in randomised clinical trials in relation to human vaccine development. DESIGN: Systematic review with meta-analysis and trial sequential analysis assessing the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SOURCES: We searched CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Science Citation Index Expanded and Conference Proceedings Citation Index-Science until 29 June 2021, and Chinese databases until September 2021. ELIGIBILITY CRITERIA: Randomised clinical trials irrespective of type, status and language of publication, with trial participants of any sex, age, ethnicity, diagnosis, comorbidity and country of residence. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias with Cochrane's RoB tool 1. Dichotomous data were analysed as risk ratios (RRs) and continuous data as mean differences. We explored both fixed-effect and random-effects models, with 95% CI. Heterogeneity was quantified with I2 statistic. We GRADE assessed the certainty of the evidence. RESULTS: We included 102 randomised clinical trials (26 457 participants). Aluminium adjuvants versus placebo or no intervention may have no effect on serious adverse events (RR 1.18, 95% CI 0.97 to 1.43; very low certainty) and on all-cause mortality (RR 1.02, 95% CI 0.74 to 1.41; very low certainty). No trial reported on quality of life. Aluminium adjuvants versus placebo or no intervention may increase adverse events (RR 1.13, 95% CI 1.07 to 1.20; very low certainty). We found no or little evidence of a difference between aluminium adjuvants versus placebo or no intervention when assessing serology with geometric mean titres or concentrations or participants' seroprotection. CONCLUSIONS: Based on evidence at very low certainty, we were unable to identify benefits of aluminium adjuvants, which may be associated with adverse events considered non-serious.

Higher vs Lower Oxygenation Strategies in Acutely Ill Adults: A Systematic Review With Meta-Analysis and Trial Sequential Analysis.

BACKGROUND: Liberal oxygen supplementation is often used in acute illness but has, in some studies, been associated with harm. RESEARCH QUESTION: The goal of this study was to assess the benefits and harms of higher vs lower oxygenation strategies in acutely ill adults. STUDY DESIGN AND METHODS: This study was an updated systematic review with meta-analysis and Trial Sequential Analysis (TSA) of randomized clinical trials. A clear differentiation (separation) was made between a higher (liberal) oxygenation and a lower (conservative) oxygenation strategy and their effects on all-cause mortality, serious adverse events, quality of life, lung injury, sepsis, and cardiovascular events at time points closest to 90 days in acutely ill adults. RESULTS: The study included 50 randomized clinical trials of 21,014 participants; 36 trials with a total of 20,166 participants contributed data to the analyses. Meta-analysis and TSAs showed no difference between higher and lower oxygenation strategies in trials at overall low risk of bias except for blinding: mortality relative risk (RR), 0.98 (95% CI, 0.89-1.09; TSA-adjusted CI, 0.86-1.12; low certainty evidence); serious adverse events RR, 0.99 (95% CI, 0.89-1.12; TSA-adjusted CI, 0.83-1.19; low certainty evidence). The corresponding summary estimates including trials with overall low and high risk of bias showed similar results. No difference was found between higher and lower oxygenation strategies in meta-analyses and TSAs regarding quality of life, lung injury, sepsis, and cardiovascular events (very low certainty evidence). INTERPRETATION: No evidence was found of beneficial or harmful effects of higher vs lower oxygenation strategies in acutely ill adults (low to very low certainty evidence). CLINICAL TRIAL REGISTRATION: PROSPERO; No.: CRD42017058011; URL: https://www.crd.york.ac.uk/prospero/.

Pharmacological interventions for prevention and management of delirium in intensive care patients: a systematic overview of reviews and meta-analyses.

OBJECTIVES: We assessed the evidence from reviews and meta-analyses of randomised clinical trials on the effects of pharmacological prevention and management of delirium in intensive care unit (ICU) patients. METHODS: We searched for reviews in July 2017 in: Cochrane Library, MEDLINE, Embase, Science Citation Index, BIOSIS Previews, CINAHL and LILACS. We assessed whether reviews were systematic according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and assessed the methodological quality using ROBIS. OUTCOME MEASURES: Primary outcomes: all-cause mortality, serious adverse events, prevention of delirium and management of delirium. SECONDARY OUTCOMES: quality of life; non-serious adverse events and cognitive function. RESULTS: We included 378 reviews: 369 narrative reviews, eight semisystematic reviews which failed on a maximum of two arbitrary PRISMA criteria and one systematic review fulfilling all 27 PRISMA criteria. For the prevention of delirium, we identified the one systematic review and eight semisystematic reviews all assessing the effects of alpha-2-agonists. None found evidence of a reduction of mortality (systematic review RR 0.99, 95% CI 0.79 to 1.24). The systematic review and three semisystematic reviews found no evidence of an effect for the prevention of delirium (systematic review RR 0.85, 0.63 to 1.14). Conversely, four semisystematic reviews found a beneficial effect. Serious adverse events, quality of life, non-serious adverse events and cognitive function were not assessed. We did not identify any systematic or semisystematic reviews addressing other pharmacological interventions for the prevention of delirium. For the management of manifest delirium, we did not identify any systematic or semisystematic review assessing any pharmacological agents. CONCLUSION: Based on systematic reviews, the evidence for the use of pharmacological interventions for prevention or management of delirium is poor or sparse. A systematic review with low risk of bias assessing the effects of pharmacological prevention of delirium and management of manifest delirium in ICU patients is urgently needed. PROSPERO REGISTRATION NUMBER: CRD42016046628.

Epigenetic perturbations in aging stem cells.

Stem cells maintain homeostasis in all regenerating tissues during the lifespan of an organism. Thus, age-related functional decline of such tissues is likely to be at least partially explained by molecular events occurring in the stem cell compartment. Some of these events involve epigenetic changes, which may dictate how an aging genome can lead to differential gene expression programs. Recent technological advances have made it now possible to assess the genome-wide distribution of an ever-increasing number of epigenetic marks. As a result, the hypothesis that there may be a causal role for an altered epigenome contributing to the functional decline of cells, tissues, and organs in aging organisms can now be explored. In this paper, we review recent developments in the field of epigenetic regulation of stem cells, and how this may contribute to aging.