Inhibitory effects of ultralow-dose sodium hypochlorite on Microcystis aeruginosa and Chlorella vulgaris: Differences in sensitivity and physiology

Throughout the COVID-19 pandemic, the application of residual free chlorine has been emphasized as an effective disinfectant;however, the discharged residual chlorine is associated with potential ecological risk at concentrations even below 0.1 mg/L. However, the influence of free chlorine at ultralow-doses (far below 0.01 mg/L) on phytoplankton remains unclear. Due to limitations of detection limit and non-linear dissolution, different dilution rates (1/500, 1/1000, 1/5000, 1/10000, and 1/50000 DR) of a NaClO stock solution (1 mg/L) were adopted to represent ultralow-dose NaClO gradients. Two typical microalgae species, cyanobacterium Microcystis aeruginosa and chlorophyta Chlorella vulgaris, were explored under solo- and co-culture conditions to analyze the inhibitory effects of NaClO on microalgae growth and membrane damage. Additionally, the effects of ultralow-dose NaClO on photosynthesis activity, intracellular reactive oxygen species (ROS) production, and esterase activity were investigated, in order to explore physiological changes and sensitivity. With an initial microalgae cell density of approximately 1 × 106 cell/mL, an inhibitory effect on M. aeruginosa was achieved at a NaClO dosage above 1/10000 DR, which was lower than that of C. vulgaris (above 1/5000 DR). The variation in membrane integrity and photosynthetic activity further demonstrated that the sensitivity of M. aeruginosa to NaClO was higher than that of C. vulgaris, both in solo- and co-culture conditions. Moreover, NaClO is able to interfere with photosynthetic activity, ROS levels, and esterase activity. Photosynthetic activity declined gradually in both microalgae species under sensitive NaClO dosage, but esterase activity increased more rapidly in M. aeruginosa, similar to the behavior of ROS in C. vulgaris. These findings of differing NaClO sensitivity and variations in physiological activity between the two microalgae species contribute to a clearer understanding of the potential ecological risk associated with ultralow-dose chlorine, and provide a basis for practical considerations. Graphical Unlabelled Image

Win ratio approach for analyzing composite time-to-event endpoint with opposite treatment effects in its components.

There is an increasing interest in the use of win ratio with composite time-to-event due to its flexibility in combining component endpoints. Exploring this flexibility further, one interesting question is in assessing the impact when there is a difference in treatment effect in the component endpoints. For example, the active treatment may prolong the time to occurrence of the negative event such as death or ventilation; meanwhile, the treatment effect may also shorten the time to achieving positive events, such as recovery or improvement. Notably, this portrays a situation where the treatment effect on time to recovery is in a different direction of benefit compared to the time to ventilation or death. Under such circumstances, if a single endpoint is used, the benefit gained for other individual outcomes is not counted and is diminished. As consequence, the study may need a larger sample size to detect a significant effect of treatment. Such a scenario can be handled by win ratio in a novel way by ranking component events, which is different from the usual composite endpoint approach such as time-to-first event. To evaluate how the different directions of treatment effect on component endpoints will impact the win ratio analysis, we use a Clayton copula-based bivariate survival simulation to investigate the correlation of component time-to-event. Through simulation, we found that compared to the marginal model using single endpoints, the win ratio analysis on composite endpoint performs better, especially when the correlation between two events is weak. Then, we applied the methodology to an infectious disease progression simulated study motivated by COVID-19. The application demonstrates that the win ratio approach offers advantages in empirical power compared to the traditional Cox proportional hazard approach when there is a difference in treatment effect in the marginal events.

Uncovering the disposable face masks as vectors of metal ions (Pb(â ¡), Cd(â ¡), Sr(â ¡)) during the COVID-19 pandemic.

The demand for disposable face masks (DFMs) increased sharply in response to the COVID-19 pandemic. However, information regarding the underlying roles of the largely discarded DFMs in the environment is extremely lacking. This study focused on the pristine and UV-aged DFMs as vectors of metal ions (Pb(Ⅱ), Cd(Ⅱ), and Sr(Ⅱ)). Further, the aging mechanism of DFMs with UV radiation as well as the interaction mechanisms between DFMs and metal ions were investigated. Results revealed that the aging process would help to promote more metal ions adsorbed onto DFMs, which was mainly attributed to the presence of oxygen-containing groups on the aged DFMs. The adsorption affinity of pristine and aged DFMs for the metal ions followed Pb(Ⅱ) > Cd(Ⅱ) > Sr(Ⅱ), which was positively corrected with the electronegativity of the metals. Interestingly, we found that even if DFMs were not disrupted, DFMs had similar or even higher adsorption affinity for metals compared with other existing microplastics. Besides, regarding environmental factors, including salinity and solution pH played a crucial role in the adsorption processes, with greater adsorption capacities for pristine and aged DFMs at higher pH values and low salinity. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and density functional theory further confirmed that the pristine DFMs interacted with the metals mainly through electrostatic interaction, while electrostatic interaction and surface complexation jointly regulated the adsorption of the metals onto aged DFMs. Overall, these findings would help to evaluate environmental behaviors and risks of DFMs associated with metals.

Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial.

BACKGROUND: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. METHODS: This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31-0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33-0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. INTERPRETATION: In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. FUNDING: Eli Lilly and Company.

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. METHODS: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. INTERPRETATION: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. FUNDING: Eli Lilly and Company. TRANSLATIONS: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Estimands, Handling of Missing Data and Impact on Assumed Effect Size and Power in Pivotal COVID-19 Treatment Trials.

Estimands play an important role for aligning study objectives, study design and analyses through a precise definition of the quantity of interest. For COVID-19 studies, apart from intercurrent events, high volume of missing data has been observed. We explore their impact on several estimands through a synthetic COVID-19 data generated from a discrete-time multi-state model. We compare estimators of these estimands based on their ability to closely match the true response rates and retain assumed power. The final choice of the estimand then needs to be aligned with clinically meaningful quantities of interest to patients, clinicians, regulators and payers.