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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 -
Critical Care and Resuscitation :... Sep 2023The effect of conservative vs. liberal oxygen therapy on outcomes of intensive care unit (ICU) patients with hypoxic ischaemic encephalopathy (HIE) is uncertain and will...
BACKGROUND
The effect of conservative vs. liberal oxygen therapy on outcomes of intensive care unit (ICU) patients with hypoxic ischaemic encephalopathy (HIE) is uncertain and will be evaluated in the Low Oxygen Intervention for Cardiac Arrest injury Limitation (LOGICAL) trial.
OBJECTIVE
The objective of this study was to summarise the protocol and statistical analysis plans for the LOGICAL trial.
DESIGN SETTING AND PARTICIPANTS
LOGICAL is a randomised clinical trial in adults in the ICU who are comatose with suspected HIE (i.e., those who have not obeyed commands following return of spontaneous circulation after a cardiac arrest where there is clinical concern about possible brain damage). The LOGICAL trial will include 1400 participants and is being conducted as a substudy of the Mega Randomised registry trial comparing conservative vs. liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX).
MAIN OUTCOME MEASURES
The primary outcome is survival with favourable neurological function at 180 days after randomisation as measured with the Extended Glasgow Outcome Scale (GOS-E). A favourable neurological outcome will be defined as a GOS-E score of lower moderate disability or better (i.e. a GOS-E score of 5-8). Secondary outcomes include survival time, day 180 mortality, duration of invasive mechanical ventilation, ICU length of stay, hospital length of stay, the proportion of patients discharged home, quality of life assessed at day 180 using the EQ-5D-5L, and cognitive function assessed at day 180 using the Montreal Cognitive Assessment (MoCA-blind).
CONCLUSIONS
The LOGICAL trial will provide reliable data on the impact of conservative vs. liberal oxygen therapy in ICU patients with suspected HIE following resuscitation from a cardiac arrest. Prepublication of the LOGICAL protocol and statistical analysis plan prior to trial conclusion will reduce the potential for outcome-reporting or analysis bias.
TRIAL REGISTRATION
Australian and New Zealand Clinical Trials Registry (ACTRN12621000518864).
PubMed: 37876368
DOI: 10.1016/j.ccrj.2023.06.007 -
The Lancet Regional Health. Western... Dec 2023HIV self-testing (HIVST) offers potential solutions to challenges associated with site-based HIV testing (SBHT). However, the effectiveness of HIVST as an HIV prevention...
Online distribution of HIV self-testing kits to promote HIV testing among men who have sex with men discontinuing pre-exposure prophylaxis after demonstration project completion in China: a multicentre open-label randomized controlled trial.
BACKGROUND
HIV self-testing (HIVST) offers potential solutions to challenges associated with site-based HIV testing (SBHT). However, the effectiveness of HIVST as an HIV prevention strategy for men who have sex with men (MSM) discontinuing pre-exposure prophylaxis (PrEP) after the completion of PrEP demonstration project has rarely been assessed.
METHODS
The China Real-world Study of Oral PrEP (CROPrEP) project was conducted in four cities in China. Participants were directed to community resources to continue their PrEP medication after the discontinuation of project-provided PrEP at the last CROPrEP visit. We conducted a multicentre open-label randomized controlled trial among MSM who had discontinued PrEP induced by the completion of CROPrEP. Eligible participants were randomly assigned to either the intervention group or the control group (1:1). Participants received regular health education and behavioural interventions throughout the trial. The intervention group was given a link to order free HIVST kits online, while the control group received information about free SBHT. Both groups completed internet-based follow-up surveys at three and six months. The primary outcome was the proportion of participants who underwent HIV testing during the six-month follow-up period. This trial was registered at chictr.org.cn (ChiCTR2000038416).
FINDINGS
Between November 2020 and January 2021, we recruited a total of 620 participants (300 in the intervention group and 320 in the control group). The follow-up completion rates were 99·0% and 95·0% in the intervention and control groups, respectively. At baseline, the median age of participants was 32 (interquartile range: 26-37), and 77·7% underwent HIV testing in the past three months. The proportion of participants who underwent HIV testing in the past three months was higher in the intervention group than in the control group at both the three-month (adjusted risk difference [RD]: 36·7, 95% confidence interval [CI]: 35·1-38·5, p < 0·001) and six-month (RD: 26·7, 95% CI: 24·6-28·7 p < 0·001) follow-up periods.
INTERPRETATION
Our study suggests that providing online distribution of HIVST kits for MSM with PrEP discontinuation induced by completion of the PrEP project effectively promoted HIV testing. This digital approach improves access to HIV testing for MSM and can be applicable to other settings where MSM turn to online public health services.
FUNDING
The study was funded by the Fund of National Natural Science Foundation of China; the Mega-Projects of National Science Research for the 13th Five-Year Plan; and the Liaoning Revitalization Talents Program, China.
PubMed: 37867621
DOI: 10.1016/j.lanwpc.2023.100922 -
Plant Phenomics (Washington, D.C.) 2023Rice () is an essential stable food for many rice consumption nations in the world and, thus, the importance to improve its yield production under global climate...
Panicle-Cloud: An Open and AI-Powered Cloud Computing Platform for Quantifying Rice Panicles from Drone-Collected Imagery to Enable the Classification of Yield Production in Rice.
Rice () is an essential stable food for many rice consumption nations in the world and, thus, the importance to improve its yield production under global climate changes. To evaluate different rice varieties' yield performance, key yield-related traits such as panicle number per unit area (PNpM) are key indicators, which have attracted much attention by many plant research groups. Nevertheless, it is still challenging to conduct large-scale screening of rice panicles to quantify the PNpM trait due to complex field conditions, a large variation of rice cultivars, and their panicle morphological features. Here, we present Panicle-Cloud, an open and artificial intelligence (AI)-powered cloud computing platform that is capable of quantifying rice panicles from drone-collected imagery. To facilitate the development of AI-powered detection models, we first established an open diverse rice panicle detection dataset that was annotated by a group of rice specialists; then, we integrated several state-of-the-art deep learning models (including a preferred model called Panicle-AI) into the Panicle-Cloud platform, so that nonexpert users could select a pretrained model to detect rice panicles from their own aerial images. We trialed the AI models with images collected at different attitudes and growth stages, through which the right timing and preferred image resolutions for phenotyping rice panicles in the field were identified. Then, we applied the platform in a 2-season rice breeding trial to valid its biological relevance and classified yield production using the platform-derived PNpM trait from hundreds of rice varieties. Through correlation analysis between computational analysis and manual scoring, we found that the platform could quantify the PNpM trait reliably, based on which yield production was classified with high accuracy. Hence, we trust that our work demonstrates a valuable advance in phenotyping the PNpM trait in rice, which provides a useful toolkit to enable rice breeders to screen and select desired rice varieties under field conditions.
PubMed: 37850120
DOI: 10.34133/plantphenomics.0105 -
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 -
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 -
European Journal of Pharmaceutical... Dec 2023Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that...
Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.
Topics: Adult; Humans; Antiviral Agents; COVID-19; Enzyme Inhibitors; Healthy Volunteers; Protease Inhibitors; Ritonavir; SARS-CoV-2
PubMed: 37783378
DOI: 10.1016/j.ejps.2023.106598 -
Bipolar Disorders May 2024Few studies have systematically examined the safety and effectiveness of antidepressant versus mood stabilizer monotherapy of bipolar II depression. To date, there are... (Meta-Analysis)
Meta-Analysis
Multi-trial, aggregated, individual participant data mega-analysis of short-term antidepressant versus mood stabilizer monotherapy of bipolar type II major depressive episode.
BACKGROUND
Few studies have systematically examined the safety and effectiveness of antidepressant versus mood stabilizer monotherapy of bipolar II depression. To date, there are no aggregated or mega-analyses of prospective trials of individual participant-level data (IPD) to inform future treatment guidelines on the relative safety and effectiveness of antidepressant or lithium monotherapy.
METHODS
Data from a series of four independent, similarly designed trials of antidepressant or lithium monotherapy (where longitudinal IPD were available) (n = 393) were aggregated into an IPD dataset (i.e., mega-analysis). Hierarchical log-linear growth models were used to analyze primary outcome of change over time in Hamilton Rating Scale for Depression (HRSD) scores; while secondary outcomes examined Clinical Global Impressions severity (CGI/S) and change (CGI/C) scores, and change over time in Young Mania Rating (YMR) scores.
RESULTS
Relative to lithium monotherapy, antidepressant monotherapy demonstrated significantly greater symptom reduction on HRSD scores across time (b = -2.33, t = -6.68, p < 0.0001), significantly greater symptom reduction on the CGI/S across time (b = -0.414, t = -6.32, p < 0.001), and a significant improvement in CGI/C across time (b = -0.47, t = -7.43, p < 0.0001). No differences were observed in change over time for YMR scores between antidepressant and lithium monotherapy (b = 0.06, t = 0.49, p = 0.62).
CONCLUSION
Findings from this IPD mega-analysis of bipolar II depression trials suggest a divergence from current evidence-based guidelines recommending combined mood stabilizer plus antidepressant therapy. The current mega-analysis suggests that antidepressant monotherapy may provide superior short-term effectiveness without clinically meaningful increase in treatment-emergent hypomanic symptoms compared to lithium monotherapy.
Topics: Humans; Bipolar Disorder; Antidepressive Agents; Adult; Male; Female; Middle Aged; Antimanic Agents; Depressive Disorder, Major; Treatment Outcome
PubMed: 37749069
DOI: 10.1111/bdi.13378 -
Environment International Oct 2023Exclusive clean fuel use is essential for realizing health and other benefits but is often unaffordable. Decreasing household-level fuel needs could make exclusive clean...
BACKGROUND
Exclusive clean fuel use is essential for realizing health and other benefits but is often unaffordable. Decreasing household-level fuel needs could make exclusive clean fuel use more affordable, but there is a lack of knowledge on the amount of fuel savings that could be achieved through fuel conservation behaviors relevant to rural settings in low- and middle-income countries.
METHODS
Within a trial in Peru, we trained a random half of intervention participants, who had previously received a liquefied petroleum gas (LPG) stove and were purchasing their own fuel, on fuel conservation strategies. We measured the amount of fuel and mega joules (MJ) of energy consumed by all participants, including control participants who were receiving free fuel from the trial. We administered surveys on fuel conservation behaviors and assigned a score based on the number of behaviors performed.
RESULTS
Intervention participants with the training had a slightly higher conservation score than those without (7.2 vs. 6.6 points; p = 0.07). Across all participants, average daily energy consumption decreased by 9.5 MJ for each 1-point increase in conservation score (p < 0.001). Among households who used exclusively LPG (n = 99), each 1-point increase in conservation score was associated with a 0.04 kg decrease in LPG consumption per household per day (p = 0.03). Using pressure cookers and heating water in the sun decreased energy use, while using clay pots and forgetting to close stove knobs increased energy use.
CONCLUSION
Our findings suggest that a household could save 1.16 kg of LPG per month for each additional fuel conservation behavior, for a maximum potential savings of 8.1 kg per month. Fuel conservation messaging could be integrated into national household energy policies to increase the affordability of exclusive clean fuel use, and subsequently achieve the environmental and health benefits that could accompany such a transition.
Topics: Humans; Air Pollution, Indoor; Household Articles; Cooking; Petroleum; Public Policy; Costs and Cost Analysis
PubMed: 37748372
DOI: 10.1016/j.envint.2023.108223 -
Signal Transduction and Targeted Therapy Sep 2023During the ongoing pandemic, providing treatment consisting of effective, low-cost oral antiviral drugs at an early stage of SARS-CoV-2 infection has been a priority for...
During the ongoing pandemic, providing treatment consisting of effective, low-cost oral antiviral drugs at an early stage of SARS-CoV-2 infection has been a priority for controlling COVID-19. Although Paxlovid and molnupiravir have received emergency approval from the FDA, some side effect concerns have emerged, and the possible oral agents are still limited, resulting in optimized drug development becoming an urgent requirement. An oral remdesivir derivative, VV116, has been reported to have promising antiviral effects against SARS-CoV-2 and positive therapeutic outcomes in clinical trials. However, whether VV116 has broad-spectrum anti-coronavirus activity and potential synergy with other drugs is not clear. Here, we uncovered the broad-spectrum antiviral potency of VV116 against SARS-CoV-2 variants of concern (VOCs), HCoV-OC43, and HCoV-229E in various cell lines. In vitro drug combination screening targeted RdRp and proteinase, highlighting the synergistic effect of VV116 and nirmatrelvir on HCoV-OC43 and SARS-CoV-2. When co-administrated with ritonavir, the combination of VV116 and nirmatrelvir showed significantly enhanced antiviral potency with noninteracting pharmacokinetic properties in mice. Our findings will facilitate clinical treatment with VV116 or VV116+nirmatrelvir combination to fight coronavirus infection.
Topics: Humans; Animals; Mice; COVID-19; SARS-CoV-2; Antiviral Agents; Coronavirus OC43, Human
PubMed: 37735468
DOI: 10.1038/s41392-023-01587-1