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JAMA Pediatrics Apr 2021Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP).
OBJECTIVE
To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants.
DESIGN, SETTING, AND PARTICIPANTS
The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020.
INTERVENTIONS
Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age.
MAIN OUTCOMES AND MEASURES
The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth.
RESULTS
A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died.
CONCLUSIONS AND RELEVANCE
This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03201588.
Topics: Arachidonic Acid; Dietary Fats; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Enteral Nutrition; Female; Humans; Infant, Newborn; Infant, Premature; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Patient Acuity; Poisson Distribution; Retinopathy of Prematurity; Treatment Outcome
PubMed: 33523106
DOI: 10.1001/jamapediatrics.2020.5653 -
Critical Care (London, England) Oct 2023Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown.
METHODS
We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score.
RESULTS
We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes.
CONCLUSION
In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.
Topics: Humans; Shock, Septic; Ascorbic Acid; Australia; Sepsis; Double-Blind Method; Vasoconstrictor Agents
PubMed: 37828547
DOI: 10.1186/s13054-023-04644-x -
Pathogens and Global Health Feb 2021Zika virus (ZIKV) is an emerging arthropod-borne flavivirus that, upon infection, results in teratogenic effects and neurological disorders. ZIKV infections pose serious... (Review)
Review
Zika virus (ZIKV) is an emerging arthropod-borne flavivirus that, upon infection, results in teratogenic effects and neurological disorders. ZIKV infections pose serious global public health concerns, prompting scientists to increase research on antivirals and vaccines against the virus. These efforts are still ongoing as the pathogenesis and immune evasion mechanisms of ZIKV have not yet been fully elaborated. Currently, no specific vaccines or drugs have been approved for ZIKV; however, some are undergoing clinical trials. Notably, several strategies have been used to develop antivirals, including drugs that target viral and host proteins. Additionally, drug repurposing is preferred since it is less costly and takes less time than other strategies because the drugs used have already been approved for human use. Likewise, different platforms have been evaluated for the design of vaccines, including DNA, mRNA, peptide, protein, viral vectors, virus-like particles (VLPSs), inactivated-virus, and live-attenuated virus vaccines. These vaccines have been shown to induce specific humoral and cellular immune responses and reduce viremia and viral RNA both and . Importantly, most of these vaccines have entered clinical trials. Understanding the viral disease mechanism will provide better strategies for developing therapeutic agents against ZIKV. This review provides a comprehensive summary of the viral pathogenesis of ZIKV and current advancements in the development of vaccines and drugs against this virus.
Topics: Antiviral Agents; Clinical Trials as Topic; Drug Repositioning; Humans; RNA, Viral; Vaccines, Attenuated; Viral Vaccines; Zika Virus; Zika Virus Infection
PubMed: 33191867
DOI: 10.1080/20477724.2020.1845005 -
Clinical Nutrition (Edinburgh, Scotland) Jun 2023Preterm infants risk deficits of long-chain polyunsaturated fatty acids (LCPUFAs) that may contribute to morbidities and hamper neurodevelopment. We aimed to determine... (Randomized Controlled Trial)
Randomized Controlled Trial
Modification of serum fatty acids in preterm infants by parenteral lipids and enteral docosahexaenoic acid/arachidonic acid: A secondary analysis of the Mega Donna Mega trial.
BACKGROUND & AIM
Preterm infants risk deficits of long-chain polyunsaturated fatty acids (LCPUFAs) that may contribute to morbidities and hamper neurodevelopment. We aimed to determine longitudinal serum fatty acid profiles in preterm infants and how the profiles are affected by enteral and parenteral lipid sources.
METHODS
Cohort study analyzing fatty acid data from the Mega Donna Mega study, a randomized control trial with infants born <28 weeks of gestation (n = 204) receiving standard nutrition or daily enteral lipid supplementation with arachidonic acid (AA):docosahexaenoic acid (DHA) (100:50 mg/kg/day). Infants received an intravenous lipid emulsion containing olive oil:soybean oil (4:1). Infants were followed from birth to postmenstrual age 40 weeks. Levels of 31 different fatty acids from serum phospholipids were determined by GC-MS and reported in relative (mol%) and absolute concentration (μmol l) units.
RESULTS
Higher parenteral lipid administration resulted in lower serum proportion of AA and DHA relative to other fatty acids during the first 13 weeks of life (p < 0.001 for the 25th vs the 75th percentile). The enteral AA:DHA supplement increased the target fatty acids with little impact on other fatty acids. The absolute concentration of total phospholipid fatty acids changed rapidly in the first weeks of life, peaking at day 3, median (Q1-Q3) 4452 (3645-5466) μmol l, and was positively correlated to the intake of parenteral lipids. Overall, infants displayed common fatty acid trajectories over the study period. However, remarkable differences in fatty acid patterns were observed depending on whether levels were expressed in relative or absolute units. For example, the relative levels of many LCPUFAs, including DHA and AA, declined rapidly after birth while their absolute concentrations increased in the first week of life. For DHA, absolute levels were significantly higher compared to cord blood from day 1 until postnatal week 16 (p < 0.001). For AA, absolute postnatal levels were lower compared to cord blood from week 4 throughout the study period (p < 0.05).
CONCLUSIONS
Our data show that parenteral lipids aggravate the postnatal loss of LCPUFAs seen in preterm infants and that serum AA available for accretion is below that in utero. Further research is needed to establish optimal postnatal fatty acid supplementation and profiles in extremely preterm infants to promote development and long-term health.
CLINICAL TRIAL REGISTRY
ClinicalTrials.gov, identifier: NCT03201588.
Topics: Infant; Infant, Newborn; Humans; Docosahexaenoic Acids; Fatty Acids; Arachidonic Acid; Cohort Studies; Infant, Extremely Premature; Phospholipids
PubMed: 37120902
DOI: 10.1016/j.clnu.2023.04.020 -
The American Journal of Psychiatry Jan 2023The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials.
METHODS
A systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included.
RESULTS
A total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a "replication crisis."
CONCLUSIONS
There is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic "big data" analyses of multiple potential biomarkers could accelerate discovery.
Topics: Humans; Autism Spectrum Disorder; Biomarkers; Phenotype; Magnetic Resonance Imaging; Research Design
PubMed: 36475375
DOI: 10.1176/appi.ajp.21100992 -
Revista Peruana de Medicina... 2020COVID-19 represents a global crisis. Rapidly conducting a clinical trial with the rigor necessary to obtain reliable results requires the collaboration of various... (Randomized Controlled Trial)
Randomized Controlled Trial
COVID-19 represents a global crisis. Rapidly conducting a clinical trial with the rigor necessary to obtain reliable results requires the collaboration of various participants involved in the development, evaluation and authorization of clinical trials (CT) such as the trial sponsor, researchers, regulatory authority and the ethics committee (EC). Carrying out these studies is not only scientifically appropriate, but an ethical and moral obligation to guarantee our patients effective treatment. SOLIDARITY is a mega clinical trial that recruited thousands of subjects with moderate to severe disease, who were randomly assigned to one of the treatment groups under evaluation, including hydroxychloroquine, lopinavir/ritonavir associated or not with interferon; or remdesivir compared to standard therapy. Peru has joined the list of countries where the trial will be reproduced, through which it will be possible to quickly identify if any of these drugs offers a real benefit to patients.
Topics: Antiviral Agents; COVID-19; Coronavirus Infections; Drug Therapy, Combination; Humans; International Cooperation; Pandemics; Peru; Pneumonia, Viral; Severity of Illness Index; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32876229
DOI: 10.17843/rpmesp.2020.372.5546 -
European Archives of Paediatric... Feb 2018Biodentine™ has frequently been acknowledged in the literature as a promising material and serves as an important representative of tricalcium silicate based cements... (Review)
Review
INTRODUCTION
Biodentine™ has frequently been acknowledged in the literature as a promising material and serves as an important representative of tricalcium silicate based cements used in dentistry.
AIM
To provide an update on the physical and biological properties of Biodentine™ and to compare these properties with those of other tricalcium silicate cements namely, different variants of mineral trioxide aggregate (MTA) such as ProRoot MTA, MTA Angelus, Micro Mega MTA (MM-MTA), Retro MTA, Ortho MTA, MTA Plus, GCMTA, MTA HP and calcium enriched mixture (CEM), Endosequence and Bioaggregate™.
STUDY DESIGN
A comprehensive literature search for publications from November 20, 2013 to November 20, 2016 was performed by two independent reviewers on Medline (PubMed), Embase, Web of Science, CENTRAL (Cochrane), SIGLE, SciELO, Scopus, Lilacs and clinicaltrials.gov. Electronic and hand search was carried out to identify randomised control trials (RCTs), case control studies, case series, case reports, as well as in vitro and animal studies published in the English language.
CONCLUSIONS
The enhanced physical and biologic properties of Biodentine™ could be attributed to the presence of finer particle size, use of zirconium oxide as radiopacifier, purity of tricalcium silicate, absence of dicalcium silicate, and the addition of calcium chloride and hydrosoluble polymer. Furthermore, as Biodentine™ overcomes the major drawbacks of MTA it has great potential to revolutionise the different treatment modalities in paediatric dentistry and endodontics especially after traumatic injuries. Nevertheless, high quality long-term clinical studies are required to facilitate definitive conclusions.
Topics: Aluminum Compounds; Animals; Calcium Compounds; Dental Cements; Drug Combinations; Humans; Oxides; Particle Size; Pulp Capping and Pulpectomy Agents; Silicates
PubMed: 29372451
DOI: 10.1007/s40368-018-0328-x -
Journal of the Royal College of... 1995
Topics: Clinical Protocols; Controlled Clinical Trials as Topic; Randomized Controlled Trials as Topic
PubMed: 7473339
DOI: No ID Found -
British Heart Journal Oct 1992
Review
Topics: Adrenergic beta-Antagonists; Anticoagulants; Aspirin; Clinical Trials as Topic; Humans; Meta-Analysis as Topic; Myocardial Infarction; Thrombolytic Therapy
PubMed: 1360226
DOI: 10.1136/hrt.68.10.352 -
Critical Care and Resuscitation :... Mar 2023The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults who have nonhypoxic ischaemic encephalopathy acute brain injuries and...
Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with nonhypoxic ischaemic acute brain injuries and conditions in the intensive care unit (Mega-ROX Brains).
BACKGROUND
The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults who have nonhypoxic ischaemic encephalopathy acute brain injuries and conditions and are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain.
OBJECTIVE
The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Brains trial.
DESIGN SETTING AND PARTICIPANTS
Mega-ROX Brains is an international randomised clinical trial, which will be conducted within an overarching 40,000-participant, registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol between 7500 and 9500 participants with nonhypoxic ischaemic encephalopathy acute brain injuries and conditions who are receiving unplanned invasive mechanical ventilation in the ICU.
MAIN OUTCOME MEASURES
The primary outcome is in-hospital all-cause mortality up to 90 d from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home.
RESULTS AND CONCLUSIONS
Mega-ROX Brains will compare the effect of conservative vs. liberal oxygen therapy regimens on 90-day in-hospital mortality in adults in the ICU with acute brain injuries and conditions. The protocol and planned analyses are reported here to mitigate analysis bias.
TRIAL REGISTRATION
Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976).
PubMed: 37876994
DOI: 10.1016/j.ccrj.2023.04.011