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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 -
European Journal of Heart Failure Sep 2020Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast... (Meta-Analysis)
Meta-Analysis
AIMS
Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power.
METHODS AND RESULTS
Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients.
CONCLUSIONS
The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials.
Topics: Chronic Disease; Heart Failure; Humans; Prognosis; Registries; Stroke Volume; Ventricular Dysfunction, Left
PubMed: 32227620
DOI: 10.1002/ejhf.1780 -
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 -
Cancers Jul 2022Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was... (Review)
Review
Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has significantly improved the patients` prognosis. In particular, the use of ICIs has shown promising results and has revolutionized the treatment algorithm in HCC patients. Indeed, preclinical and clinical data have documented a high density of immunosuppressive cells and an increased expression of the programmed death-1 (PD-1) receptor and cytotoxic T-cell associated protein-4 (CTLA-4) in HCC. However, despite these observations, no validated biomarker is available and the molecular groundwork responsible for response to ICIs remains elusive. The anti-CTLA4 monoclonal antibody tremelimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab were the first ICIs to be tested in HCC. Recently, the combination of the anti-programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab demonstrated an improvement in patient outcome compared to sorafenib, becoming the standard of care in the frontline setting of advanced disease. Other immunotherapeutic agents such as pembrolizumab or the combination nivolumab-ipilimumab have shown promising results that have to be confirmed in phase III studies. Currently, the combination of different ICIs (i.e., ipilimumab, durvalumab) and anti-angiogenic agents (i.e., regorafenib, lenvatinib) is currently being tested in several trials and will hopefully revolutionize the treatment of HCC. To date, numerous studies are underway evaluating ICIs in adjuvant and neoadjuvant settings to improve survival in early and intermediate stages. Thus, this review focuses on the rationale for ICIs and their potential use for early or intermediate HCC stages.
PubMed: 35884392
DOI: 10.3390/cancers14143332 -
Frontiers in Plant Science 2022Genotype by environment interaction (GEI) is a phenomenon that occurs in heterogeneous environments that slows breeding progress by preventing the selection of superior...
Genotype by environment interaction (GEI) is a phenomenon that occurs in heterogeneous environments that slows breeding progress by preventing the selection of superior cultivars for breeding and commercialization. Therefore, the objectives of this study were to find out how GEI impacts soybean output and to identify the most adapted and stable genotypes. Moreover, to look at the possibility of other mega environments for testing in the future. The experiments were grown for two years in a four-replicated randomized block design at each environment. Over the course of several harvests, yield components, days to flowering, days to maturity, plant height, the number of pods per plants, the number of seeds per plant, hundred seed weight and grain yield per hectare were evaluated in the main for 2018 and 2019.To analyze the stability performance of the genotypes, general linear method, GGE and Additive main effect and multiplicative interaction effects analysis (AMMI) and ASV rank analysis were applied. The GGE biplot revealed that the GGE biplots explained 74.29% of the total variation distributed as,56.69% and 17.62% of sum of squares between principal component PC1 and PC2, respectively whereas, AMMI model, the first two interaction principal component axes (IPCA1 and IPCA2) explained 47.74% and 26.62% of the variation due to GEI, respectively, exposed genotypes identified the five as best performer. The results from the four distinct stability statistics AMMI biplot (G8, G2, G1, G11), ASV (G1, G11; (GSI; G9, G1, G11) and (GGE: G2, G8, G9) are taken into account together with the genotypes` grand mean. The genotypes JM-CLK/CRFD-15-SD (G8) and 5002T (G1), which rank among the best and have the highest seed output, are suitable for hybridization as a parent and commercial production. Therefore, genotypes JM-CLK/CRFD-15-SD (G8) and 5002T(G1) have the highest seed output were among the best and thus could be recommended for release as a new soybean varieties cultivation across.
PubMed: 36507436
DOI: 10.3389/fpls.2022.950992 -
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 -
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 -
Frontiers in Immunology 2022Activation of the cGAS-STING pathway by cytoplasmic DNA induces the production of Type-1 interferons. Recent advances in research suggest that the cGAS-STING pathway is... (Review)
Review
Activation of the cGAS-STING pathway by cytoplasmic DNA induces the production of Type-1 interferons. Recent advances in research suggest that the cGAS-STING pathway is involved in different parts of the cancer-immunity cycle (CIC) to promote or suppress antitumor immune responses. Combination therapy of STING agonists has made certain progress in preclinical as well as clinical trials, but the selection of combination therapy regimens remains a challenge. In this review, we summarize the role of the cGAS-STING in all aspects of CIC, and focus on the combination immunotherapy strategies of STING agonists and current unsolved challenges.
Topics: Humans; DNA; Immunotherapy; Membrane Proteins; Neoplasms; Nucleotidyltransferases
PubMed: 36353640
DOI: 10.3389/fimmu.2022.996663 -
Nature Communications Dec 2022Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose...
Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose study, comparing BNT162b2 and mRNA1273, administered four months after a third BNT162b2 dose. The primary outcomes are the levels of IgG, neutralizing antibodies, and microneutralization and the secondary outcomes are the levels of IgA and T cell activation, and clinical outcomes of SARS-CoV-2 infection and substantial symptomatic disease. Waning of the immune response is evident during follow-up, with an 11% (β = 0.89, 95% CI, 0.88-0.9) and 21% (β = 0.79, 95% CI, 0.76-0.82) multiplicative decay per week of IgG and neutralizing antibodies, respectively, in the mRNA1273 group, and of 14% (β = 0.86, 95% CI, 0.86-0.87) and 26% (β = 0.74, 95% CI, 0.72-0.76), respectively, in the BNT162b2 group. Direct neutralization of Omicron variants is low relative to ancestral strains. Cumulatively over the study period, both vaccines show little efficacy against infection but were highly efficacious against substantial symptomatic disease [89% [(IRR 0.11, 95% CI, 0.02-0.37) and 71% (IRR 0.29, 95% CI, 0.13-0.57) for mRNA1273 and BNT162b2, respectively]. These results are informative for further boosting policy-making. Trial registration numbers (clinicaltrials.gov): NCT05231005 and NCT05230953.
Topics: Humans; COVID-19 Vaccines; BNT162 Vaccine; Follow-Up Studies; Pandemics; COVID-19; SARS-CoV-2; Antibodies, Neutralizing; Immunoglobulin G; Antibodies, Viral
PubMed: 36513665
DOI: 10.1038/s41467-022-35480-2 -
ERJ Open Research May 2024COPD is a major healthcare problem and cause of mortality worldwide. COPD patients at increased mortality risk are those who are more symptomatic, have lower lung... (Review)
Review
COPD is a major healthcare problem and cause of mortality worldwide. COPD patients at increased mortality risk are those who are more symptomatic, have lower lung function and lower diffusing capacity of the lung for carbon monoxide, decreased exercise capacity, belong to the emphysematous phenotype and those who have concomitant bronchiectasis. Mortality risk seems to be greater in patients who experience COPD exacerbations and in those who suffer from concomitant cardiovascular and/or metabolic diseases. To predict the risk of death in COPD patients, several composite scores have been created using different parameters. In previous years, large studies (also called mega-trials) have evaluated the efficacy of different therapies on COPD mortality, but until recently only nonpharmaceutical interventions have proven to be effective. However, recent studies on fixed combinations of triple therapy (long-acting β-agonists, long-acting muscarinic antagonists and inhaled corticosteroids) have provided encouraging results, showing for the first time a reduction in mortality compared to dual therapies. The aim of the present review is to summarise available data regarding mortality risk in COPD patients and to describe pharmacological therapies that have shown effectiveness in reducing mortality.
PubMed: 38887682
DOI: 10.1183/23120541.00850-2023