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PloS One 2021γ-Aminobutyric acid (GABA) is a primary inhibitory neurotransmitter in the human brain. It has been shown that altered GABA concentration plays an important role in a... (Clinical Trial)
Clinical Trial
γ-Aminobutyric acid (GABA) is a primary inhibitory neurotransmitter in the human brain. It has been shown that altered GABA concentration plays an important role in a variety of psychiatric and neurological disorders. The main purpose of this study was to propose a combination of PRESS and MEGA-PRESS acquisitions for absolute GABA quantification and to compare GABA estimations obtained using total choline (tCho), total creatine (tCr), and total N-acetyl aspartate (tNAA) as the internal concentration references with water referenced quantification. The second aim was to demonstrate the fitting approach of MEGA-PRESS spectra with QuasarX algorithm using a basis set of GABA, glutamate, glutamine, and NAA in vitro spectra. Thirteen volunteers were scanned with the MEGA-PRESS sequence at 3T. Interleaved water referencing was used for quantification, B0 drift correction and to update the carrier frequency of RF pulses in real time. Reference metabolite concentrations were acquired using a PRESS sequence with short TE (30 ms) and long TR (5000 ms). Absolute concentration were corrected for cerebrospinal fluid, gray and white matter water fractions and relaxation effects. Water referenced GABA estimations were significantly higher compared to the values obtained by metabolite references. We conclude that QuasarX algorithm together with the basis set of in vitro spectra improves reliability of GABA+ fitting. The proposed GABA quantification method with PRESS and MEGA-PRESS acquisitions enables the utilization of tCho, tCr, and tNAA as internal concentration references. The use of different concentration references have a good potential to improve the reliability of GABA estimation.
Topics: Adult; Algorithms; Female; Gyrus Cinguli; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; gamma-Aminobutyric Acid
PubMed: 33449935
DOI: 10.1371/journal.pone.0240641 -
Acute Medicine & Surgery 2023Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by... (Review)
Review
Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by infectious and noninfectious insults, such as trauma, postcardiac arrest syndrome, and malignant diseases. At present, diagnosis and treatment of DIC clearly differ between Japan and Western countries; in Japan, DIC has long been considered a therapeutic target, and much evidence on DIC has been published. However, there has recently been no international consensus on whether DIC should be a therapeutic target with anticoagulant therapy. This review describes the coagulofibrinolytic system abnormalities associated with sepsis and discusses related management strategies. It also explores the reasons why DIC is perceived differently in different regions. There is a major discrepancy between diagnostic and treatment options in Japan, which are based on holistic assessments of trials, as well as the results of post hoc subgroup analyses and observational studies, and those in Western countries, which are based mainly on the results of sepsis mega trials, especially randomized controlled trials. The differences might also be due to various patient factors in each region, especially racial characteristics in thrombolytic mechanisms, and differences in interpretation of evidence for candidate drugs. Hence, Japanese researchers need to distribute their high-quality clinical research data not only to Japan but also to the rest of the world.
PubMed: 37153869
DOI: 10.1002/ams2.843 -
Nature Communications Oct 2023The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the...
The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CL inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.
Topics: Mice; Female; Male; Animals; Humans; Rats; SARS-CoV-2; Protease Inhibitors; COVID-19; Antiviral Agents; Enzyme Inhibitors
PubMed: 37833261
DOI: 10.1038/s41467-023-42102-y -
Journal of General Internal Medicine Jul 2016Over the past decade, a large body of observational evidence has suggested an association between lower vitamin D status (25-hydroxyvitamin D) and multiple acute and... (Review)
Review
Over the past decade, a large body of observational evidence has suggested an association between lower vitamin D status (25-hydroxyvitamin D) and multiple acute and chronic disorders, including cancer, multiple sclerosis, depression and respiratory tract infections. This evidence has fostered the hypothesis that increasing vitamin D intake may treat and prevent such disorders. Our objective was to perform a critical analysis of the highest-level evidence for ten common beliefs regarding vitamin D for the prevention of falls, fractures and respiratory tract infections, the reduction of cancer incidence/mortality and overall mortality, and the prevention or treatment of depression/mental well-being, rheumatoid arthritis and multiple sclerosis, as well as maximum dosing and regular testing. We searched the Cochrane Database of Systematic Reviews and PubMed (up to August 2014) for randomized controlled trials and systematic reviews/meta-analyses based on those studies. All searches were performed, all evidence reviewed and each section written by at least two authors. The evidence shows that vitamin D supplementation provides some benefit in fracture prevention (likely ∼10-15 % relative reduction), particularly at a dose ≥800 IU and with calcium; a likely benefit in the rate of falls, though it is less clear whether the number of fallers changes; and a possible small (∼5 %) relative reduction in mortality. Evidence does not support the use of vitamin D supplementation for the prevention of cancer, respiratory infections or rheumatoid arthritis. Similarly, evidence does not support vitamin D supplementation for the treatment of multiple sclerosis and rheumatoid arthritis or for improving depression/mental well-being. Regular testing of 25-hydroxyvitamin D is generally not required, and mega-doses (≥300,000 IU) appear to increase harms. Much of the evidence is at high risk of bias, with multiple flaws, including analyses of secondary endpoints, small and underpowered studies, inconsistent results and numerous other issues. Therefore, enthusiasm for a vitamin D panacea should be tempered.
Topics: Accidental Falls; Dietary Supplements; Dose-Response Relationship, Drug; Fractures, Bone; Humans; Meta-Analysis as Topic; Mortality; Observational Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Vitamin D; Vitamins
PubMed: 26951286
DOI: 10.1007/s11606-016-3645-y -
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 -
Critical Care and Resuscitation :... Jun 2022The effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in patients who require unplanned invasive mechanical ventilation in an...
Protocol and statistical analysis plan for the mega randomised registry trial research program comparing conservative versus liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX).
The effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in patients who require unplanned invasive mechanical ventilation in an intensive care unit (ICU) is uncertain and will be evaluated in the mega randomised registry trial research program (Mega-ROX). To summarise the protocol and statistical analysis plan for Mega-ROX. Mega-ROX is a 40 000-patient parallel-group, registry-embedded clinical trial in which adults who require unplanned invasive mechanical ventilation in an ICU will be randomly assigned to conservative or liberal oxygen therapy. Within this overarching trial research program, three nested parallel randomised controlled trials will be conducted. These will include patients with suspected hypoxic ischaemic encephalopathy (HIE) following resuscitation from a cardiac arrest, patients with sepsis, and patients with non-HIE acute brain injuries or conditions. The primary outcome is in-hospital allcause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and proportion of patients discharged home. Mega-ROX will compare the effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in critically ill adults who receive unplanned invasive mechanical ventilation in an ICU. The protocol and a pre-specified approach to analyses are reported here to mitigate analysis bias. Australian and New Zealand Clinical Trials Registry (ANZCTRN 12620000391976).
PubMed: 38045600
DOI: 10.51893/2022.2.OA4 -
Critical Care and Resuscitation :... Jun 2023The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned invasive mechanical ventilation in the...
Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with sepsis in the intensive care unit (Mega-ROX Sepsis).
BACKGROUND
The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned 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 Sepsis trial.
DESIGN SETTING AND PARTICIPANTS
The Mega-ROX Sepsis trial is an international randomised clinical trial that will be conducted within an overarching 40,000-patient registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We anticipate that between 10,000 and 13,000 patients with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU will be enrolled in this trial.
MAIN OUTCOME MEASURES
The primary outcome is in-hospital all-cause mortality up to 90 days 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 patients discharged home.
RESULTS AND CONCLUSIONS
Mega-ROX Sepsis will compare the effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU. The protocol and a prespecified approach to analyses are reported here to mitigate analysis bias.
PubMed: 37876605
DOI: 10.1016/j.ccrj.2023.04.008 -
Therapeutic Advances in Cardiovascular... Jun 2016Following extensive clinical research, drugs affecting the renin-angiotensin system have been used for the treatment of patients with congestive heart failure,... (Review)
Review
Following extensive clinical research, drugs affecting the renin-angiotensin system have been used for the treatment of patients with congestive heart failure, myocardial infarction, hypertension, diabetic nephropathy, chronic renal failure and for reducing the risk of developing major cardiovascular (CV) events. This review examines all mega trials (those involving >1000 patients) and smaller pivotal trials involving angiotensin-converting enzyme inhibitors (ACE-Is; 25 mega trials) and angiotensin receptor blockers (ARBs; 27 mega trials) to provide perspective on the huge database of evidence that has accumulated on the use of these drugs. Our review demonstrates that ACE-Is and ARBs are generally as effective as conventional therapies in the treatment of hypertension, but offer additional cardioprotective benefits in patients with heart failure, and in those who have experienced myocardial infarction. Also, both ACE-Is and ARBs are capable of renal protection in addition to their blood-pressure-lowering effects. Although ACE-Is and ARBs provide major benefits to CV patients, doubts remain over the concept of blood-pressure-independent CV protection offered by both classes of drugs. ACE-Is and ARBs appear to be equally effective with respect to morbidity and mortality endpoints, but ARBs are better tolerated. Considering the available evidence, the combined use of an ACE-I and ARB should be avoided and full doses of either ACE-I or ARB should be aimed for as evidence suggests they provide a greater prognostic benefit.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Stroke
PubMed: 27271312
DOI: 10.1177/1753944716644131 -
BMJ Open Jul 2022Secondary schools have the transformative potential to advance adolescent nutrition and provide a unique entry point for nutrition interventions to reach adolescents and...
Meals, Education, and Gardens for In-School Adolescents (MEGA): study protocol for a cluster randomised trial of an integrated adolescent nutrition intervention in Dodoma, Tanzania.
INTRODUCTION
Secondary schools have the transformative potential to advance adolescent nutrition and provide a unique entry point for nutrition interventions to reach adolescents and their families and communities. Integrated school nutrition interventions offer promising pathways towards improving adolescent nutrition status, food security and building sustainable skill sets.
METHODS AND ANALYSIS
The Meals, Education, and Gardens for In-School Adolescents (MEGA) project aims to implement and evaluate an integrated, school-based nutrition intervention package among secondary schools in the Chamwino District of Dodoma, Tanzania. MEGA is a cluster-randomised controlled trial, including six public secondary schools assigned to three different arms. Two schools will receive the full intervention package, including school meals, school gardens, nutrition education and community workshops. Two schools will receive the partial intervention package, including the school garden, nutrition education and community workshops. Two schools will serve as the controls and will not receive any intervention. The intervention will be implemented for one academic year. Baseline and end-line quantitative data collection will include 750 adolescents and 750 parents. The domains of outcomes for adolescents will include haemoglobin concentrations, anthropometry, educational outcomes and knowledge, attitudes and practices regarding nutrition, agriculture and health. The domains of outcomes for parents will include knowledge, attitudes and practices of nutrition, agriculture and health. End-line focus group discussions will be conducted among selected adolescents, parents and teachers to assess the facilitators and barriers associated with the intervention.
ETHICS AND DISSEMINATION
This study was approved by the Institutional Review Board at Harvard T.H. Chan School of Public Health (approval number: IRB20-1623), the Institutional Research Review Committee at the University of Dodoma (approval number: MA.84/261/02) and the Tanzania National Institute for Medical Research (approval number: NIMR/HO/R.8a/Vol. IX/3801). A manuscript with the research findings will be developed for publication. Local dissemination meetings will be held with key stakeholders.
TRIAL REGISTRATION NUMBER
NCT04788303.; ClinicalTrials.gov Identifier.
Topics: Adolescent; Educational Status; Gardens; Humans; Meals; Randomized Controlled Trials as Topic; School Health Services; Schools; Tanzania
PubMed: 35798513
DOI: 10.1136/bmjopen-2022-062085 -
The New England Journal of Medicine Sep 2017Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization.
RESULTS
During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.
CONCLUSIONS
Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .).
Topics: Aged; Anticholesteremic Agents; Atherosclerosis; Cholesterol; Cholesterol Ester Transfer Proteins; Coronary Disease; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Kaplan-Meier Estimate; Male; Medication Adherence; Middle Aged; Oxazolidinones
PubMed: 28847206
DOI: 10.1056/NEJMoa1706444