Organophosphate triesters and their diester degradation products in the atmosphere-A critical review.

Organophosphate triesters (tri-OPEs) have found substantial use as plasticizers and flame retardants in commercial and industrial products. Despite upcoming potential restrictions on use of OPEs, widespread environmental contamination is likely for the foreseeable future. Organophosphate diesters (di-OPEs) are known biotic or abiotic degradation products of tri-OPEs. In addition, direct use of di-OPEs as commercial products also contributes to their presence in the atmosphere. We review the available data on contamination with tri-OPEs and di-OPEs in both indoor and outdoor air. Concentrations of tri-OPEs in indoor air exceed those in outdoor air. The widespread discovery of tri-OPE traces in polar regions and oceans is noteworthy and is evidence that they undergo long-range transport. There are only two studies on di-OPEs in outdoor air and no studies on di-OPEs in indoor air until now. Current research on di-OPEs in indoor and outdoor air is urgently needed, especially in countries with potentially high exposure to di-OPEs such as the UK and the US. Di-OPE concentrations are higher at e-waste dismantling areas than at surrounding area. We also summarise the methods employed for sampling and analysis of OPEs in the atmosphere and assess the relative contribution to atmospheric concentrations of di-OPEs made by environmental degradation of triesters, compared to the presence of diesters as by-products in commercial triester products. Finally, we identify shortcomings of current research and provide suggestions for future research.

Impact of Legislation on Brominated Flame Retardant Concentrations in UK Indoor and Outdoor Environments: Evidence for Declining Indoor Emissions of Some Legacy BFRs.

Concentrations of polybrominated diphenyl ethers, hexabromocyclododecane (HBCDD), and novel brominated flame retardants (NBFRs) were measured in indoor dust, indoor air, and outdoor air in Birmingham, UK. Concentrations of ΣBFRs ranged from 490 to 89,000 ng/g, 46-14,000 pg/m3, and 22-11,000 pg/m3, respectively, in UK indoor dust, indoor air, and outdoor air. BDE-209 and decabromodiphenyl ethane (DBDPE) were the main contributors. The maximum concentration of DBDPE (10,000 pg/m3) in outdoor air is the highest reported anywhere to date. In contrast with previous studies of outdoor air in Birmingham, we observed significant correlations between concentrations of tri- to hepta-BDEs and HBCDD and temperature. This may suggest that primary emissions from ongoing use of these BFRs have diminished and that secondary emissions (e.g., evaporation from soil) are now a potentially major source of these BFRs in outdoor air. Conversely, the lack of significant correlations between temperature and concentrations of BDE-209 and DBDPE may indicate that ongoing primary emissions from indoor sources remain important for these BFRs. Further research to clarify the relative importance of primary and secondary sources of BFRs to outdoor air is required. Comparison with earlier studies in Birmingham reveals significant (p < 0.05) declines in concentrations of legacy BFRs, but significant increases for NBFRs over the past decade. While there appear minimal health burdens from BFR exposure for UK adults, dust ingestion of BDE-209 may pose a significant risk for UK toddlers.

Translational PK/PD for the Development of Novel Antibiotics-A Drug Developer's Perspective.

Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a lean clinical efficacy dataset is complemented by nonclinical data as supportive evidence of efficacy. In this context, translational Pharmacokinetic/Pharmacodynamic (PK/PD) plays a key role and is a major contributor to a "robust" nonclinical package. The classical PK/PD index approach, proven successful for established classes of antibiotics, is at the core of recent antibiotic approvals and the current antibacterial PK/PD guidelines by regulators. Nevertheless, in the case of novel antibiotics with a novel Mechanism of Action (MoA), there is no prior experience with the PK/PD index approach as the basis for translating nonclinical efficacy to clinical outcome, and additional nonclinical studies and PK/PD analyses might be considered to increase confidence. In this review, we discuss the value and limitations of the classical PK/PD approach and present potential risk mitigation activities, including the introduction of a semi-mechanism-based PK/PD modeling approach. We propose a general nonclinical PK/PD package from which drug developers might choose the studies most relevant for each individual candidate in order to build up a "robust" nonclinical PK/PD understanding.

Neural network for evaluation of the impact of the UK COVID-19 national lockdown on atmospheric concentrations of PAHs and PBDEs.

The impact of measures to restrict population mobility during the COVID-19 pandemic on atmospheric concentrations of polycyclic aromatic hydrocarbons (PAH) and brominated flame retardants (BFRs) is poorly understood. This study analyses the effects of meteorological parameters and mobility restrictions during the COVID-19 pandemic on concentrations of PAH and BFRs at the University of Birmingham in the UK utilising a neural network (self-organising maps, SOM). Air sampling was performed using Polyurethane Foam (PUF) disk passive samplers between October 2019 and January 2021. Data on concentrations of PAH and BFRs were analysed using SOM and Spearman's rank correlation. Data on meteorological parameters (air temperature, wind, and relative humidity) and mobility restrictions during the pandemic were included in the analysis. Decabromodiphenyl ether (BDE-209) was the most abundant polybrominated diphenyl ether (PBDE) (23-91% Σ7PBDEs) but was detected at lower absolute concentrations (4.2-35.0 pg m-3) than in previous investigations in Birmingham. Air samples were clustered in five groups based on SOM analysis and the effects of meteorology and pandemic-related restrictions on population mobility could be visualised. Concentrations of most PAH decreased during the early stages of the pandemic when mobility was most restricted. SOM analysis also helped to identify the important influence of wind speed on contaminant concentrations, contributing to reduce the concentration of all analysed pollutants. In contrast, concentrations of most PBDEs remained similar or increased during the first COVID-19 lockdown which was attributed to their primarily indoor sources that were either unaffected or increased during lockdown.

Single injection by LC-ESI-MS/MS for simultaneous determination of organophosphate tri- and di-esters in plant tissue based on ultrasonic-assisted sequential extraction and single-step purification.

A novel methodology based on ultrasonic-assisted sequential extraction, dispersive-SPE purification, and single-injection on liquid chromatography-tandem mass spectrometry (LC-MS/MS) is proposed, for the first time, to simultaneously measure 14 tri-OPEs and 9 di-OPEs in plant tissues. The samples were successively ultrasonicated with a mixture of hexane:dichloromethane (1:1, v/v) and 8% acetic acid in acetonitrile for extracting tri- and di-OPEs purified with graphitized carbon black and quantitated on LC-MS/MS at the same time. The recoveries of targeted tri- and di-OPEs in the matrix spike ranged from 66% to 120% and 71% to 110% respectively. The proposed method was validated by processing eight types of common vegetables including spinach (Spinacia oleracea L.), lettuce (Lactuca sativa), carrot (Daucus carota var. sativa Hoffm.), sweet potato (Solanum tuberosum L.), cucumber (Cucumis sativus L.), tomato (Solanum lycopersicum L.), green beans (Phaseolus vulgaris), and cowpeas (Vigna unguiculata), with the recoveries of surrogates ranging from 84% to 98%.

Oral bemnifosbuvir (AT-527) vs placebo in patients with mild-to-moderate COVID-19 in an outpatient setting (MORNINGSKY).

Aim: This phase III study assessed the efficacy/safety/antiviral activity/pharmacokinetics of bemnifosbuvir, a novel, oral nucleotide analog to treat COVID-19. Patients & methods: Outpatient adults/adolescents with mild-to-moderate COVID-19 were randomized 2:1 to bemnifosbuvir/placebo. Time to symptom alleviation/improvement (primary outcome), risk of hospitalization/death, viral load and safety were evaluated. Results: Although the study was discontinued prematurely and did not meet its primary end point, bemnifosbuvir treatment resulted in fewer hospitalizations (71% relative risk reduction), COVID-19-related medically attended hospital visits, and COVID-19-related complications compared with placebo. No reduction in viral load was observed. The proportion of patients with adverse events was similar; no deaths occurred. Conclusion: Bemnifosbuvir showed hospitalization reduction in patients with variable disease progression risk and was well tolerated. Clinical Trial Registration: NCT04889040 (ClinicalTrials.gov).

100 years of anthropogenic impact causes changes in freshwater functional biodiversity.

Despite efforts from scientists and regulators, biodiversity is declining at an alarming rate. Unless we find transformative solutions to preserve biodiversity, future generations may not be able to enjoy nature's services. We have developed a conceptual framework that establishes the links between biodiversity dynamics and abiotic change through time and space using artificial intelligence. Here, we apply this framework to a freshwater ecosystem with a known history of human impact and study 100 years of community-level biodiversity, climate change and chemical pollution trends. We apply explainable network models with multimodal learning to community-level functional biodiversity measured with multilocus metabarcoding, to establish correlations with biocides and climate change records. We observed that the freshwater community assemblage and functionality changed over time without returning to its original state, even if the lake partially recovered in recent times. Insecticides and fungicides, combined with extreme temperature events and precipitation, explained up to 90% of the functional biodiversity changes. The community-level biodiversity approach used here reliably explained freshwater ecosystem shifts. These shifts were not observed when using traditional quality indices (e.g. Trophic Diatom Index). Our study advocates the use of high-throughput systemic approaches on long-term trends over species-focused ecological surveys to identify the environmental factors that cause loss of biodiversity and disrupt ecosystem functions.

Over long periods of time, environmental changes ­ such as chemical pollution and climate change ­ affect the diversity of organisms that live in an ecosystem, known as 'biodiversity'. Understanding the impact of these changes is challenging because they can happen slowly, their effect is only measurable after years, and historical records are limited. This can make it difficult to determine when specific changes happened, what might have driven them and what impact they might be having. One way to measure changes in biodiversity over time is by analysing traces of DNA shed by organisms. Plants, animals, and bacteria living in lakes leave behind genetic material that gets trapped and buried in the sediment at the bottom of lakes. Similarly, biocides ­ substances used to kill or control populations of living organisms ­ that run-off into lakes leach into the sediment and can be measured years later. Therefore, this sediment holds a record of life and environmental impacts in the lake over past centuries. Eastwood, Zhou et al. wanted to understand the relationship between environmental changes (such as the use of biocides and climate change) and shifts in lake biodiversity. To do so, the researchers studied a lake community that had experienced major environmental impacts over the last century (including nutrient pollution, chemical pollution and climate change), but which appeared to improve over the last few years of the 20^th century. Using machine learning to find connections over time between biodiversity and non-living environmental changes, Eastwood, Zhou et al. showed that, despite apparent recovery in water quality, the biodiversity of the lake was not restored to its original state. A combination of climate factors (such as rainfall levels and extreme temperatures) and biocide application (particularly insecticides and fungicides) explained up to 90% of the biodiversity changes that occurred in the lake. These changes had not been identified before using traditional techniques. The functional roles microorganisms played in the ecosystem (such as degradation and nitrogen metabolism) were also altered, suggesting that loss of biodiversity may lead to loss of ecosystem functions. The findings described by Eastwood, Zhou et al. can be used by environmental regulators to identify species or ecosystems at risk from environmental change and prioritise them for intervention. The approach can also be used to identify which chemicals pose the greatest threat to biodiversity. Additionally, the use of environmental DNA from sediment can provide rich historical biodiversity data, which can be used to train artificial intelligence-based models to improve predictions of how ecosystems will respond to complex environmental changes.

Analysis and subcellular distribution of organophosphate esters (OPEs) in rice tissues.

Recent studies have identified the ability of plants to uptake and translocate organophosphate esters (OPEs) within cells. In response to the increasing interest in OPEs and their occurrence in paddy fields and rice, the current study aimed to present an effective and sensitive GC-MS based methodology for quantitative determination of 11 OPEs with octanol-water coefficients ranging from 1.6 to 10. Rice was sonicated with hexane and dichloromethane, and fractionated on two columns: one consisting of neutral alumina, and neutral silica, and the other consisting of graphitized carbon black. Method precision was validated using spiked rice (n = 30) and procedural blanks (n = 9). The mean recovery of matrix spikes for all target OPEs were within 78-110% with relative standard deviation lower than 25%, with a few exceptions. This method was applied to process the wild rice (O. sativa) in which tri-n-propyl phosphate was the dominant targeted OPE. The recoveries of surrogate standards were 81 ± 17% for d12- tris(2-chloroethyl) phosphate and 95 ± 8.8% for 13C12- triphenyl phosphate. The developed method was further used to examine the recoveries of target OPEs in the subcellular structure of rice tissues, including cell wall, cell organelles, cell water-soluble fractions, and cell residue. Recoveries of most target OPEs were in the range of 50-150%; however, ion enhancement was observed for four OPEs in root and shoot tissues. Hydrophobic OPEs accumulated in the cell wall, cell residue, and cell organelles while chlorinated OPEs mainly distributed in the cell water-soluble fraction. These results provide new insight for the ecological risk assessment of OPEs in an important food staple.

Determination of polyoxymethylene-water partition coefficients for diverse organophosphate esters (OPEs) and prediction of the free-dissolved OPEs in OPE-contaminated soil.

Increasing attention on the estimation of bioavailability of organophosphate esters (OPEs) in soil or sediment has urged the development of techniques to measure soil-/sediment-associated porewater concentrations of OPEs. In this study, we investigated the sorption dynamics of 8 OPEs to polyoxymethylene (POM) spanning one order of magnitude of aqueous OPE concentrations and proposed POM-water partitioning coefficients (Kpom/w) for OPEs. The results showed that the Kpom/w values were mainly affected by the hydrophobicity of OPEs. OPEs with high solubility preferentially partitioned into the aqueous phase indicated by the low log Kpom/w values; while lipophilic OPEs were observed to be taken up by POM. The concentration of lipophilic OPEs in the aqueous phase had a strong impact on their sorption dynamics on POM, with higher aqueous concentrations accelerating the sorption dynamics and shortening the time for equilibration. We proposed that the required time to reach equilibration for targeted OPEs should be 42 d. The proposed equilibration time and Kpom/w values were further validated by applying POM to soil artificially contaminated with OPEs to measure OPEs soil-water partitioning coefficients (Ks). The variations of Ks among soil types implied the need to elucidate the effects of soil properties and chemical properties of OPEs on their distribution between soil and water in the future.

Temporal trends in concentrations of brominated flame retardants in UK foodstuffs suggest active impacts of global phase-out of PBDEs and HBCDD.

Global restrictions on use of legacy brominated flame retardants (BFRs) such as polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD) have generated demand for novel BFRs (NBFRs) as substitutes. Our research group has previously reported decreased concentrations of PBDEs and HBCDD and increased concentrations of NBFRs in UK indoor environments, suggesting that restrictions on PBDEs and HBCDD are exerting an impact. In this study, we analysed UK foodstuffs collected in 2020-21 and compared the BFR concentrations found with those found in similar samples collected in 2015 to investigate whether similar trends in BFR concentrations would be observed. Concentrations of PBDEs and HBCDD isomers detected in our samples had declined by 78-92 % and 59-97 % since the 2015 study, respectively. Moreover, concentrations of NBFRs (dominated by 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE or TBE), and bis(2-ethyl hexyl) tetrabromophthalate (BEH-TEBP or TBPH)) in UK foodstuffs increased significantly (28-1400 %) between 2015 and 2020-21. Combined, these findings suggest that restrictions on use of PBDEs and HBCDD have had a discernible impact on concentrations of these legacy BFRs and their NBFR replacements in UK foodstuffs. Interestingly, given recent reports of a significant increase in concentrations of decabromodiphenyl ethane (DBDPE) in UK house dust between 2014 and 2019, a significant decline (70-84 %) in concentrations of DBDPE was observed in UK foodstuffs.

Chlorinated organophosphate esters in Irish waste foams and fabrics: Concentrations, preliminary assessment of temporal trends and evaluation of the impact of a concentration limit value.

Concentrations of the chlorinated organophosphate esters (Cl-OPEs): tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP), and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) were measured in 273 waste synthetic foam and fabric articles collected in Ireland between 2019 and 2020. Articles examined comprised: polystyrene building insulation foam, as well as foam fillings and fabric coverings from furniture, mattresses, end-of-life vehicles, curtains, and carpets. Cl-OPEs were also measured in 156 samples from the same categories (except for building insulation foam) collected in 2015-16. Concentrations of TCIPP and TDCIPP in most samples exceeded those of TCEP; with those of TCIPP and TDCIPP generally and for some waste categories significantly (p < 0.05) higher in samples collected in 2019-20. Given potential future restrictions on use of these Cl-OPEs, we identified articles containing concentrations that exceeded 1000 mg/kg, in line with a similar limit that at the time of sample collection existed for some brominated flame retardants within the European Union. In 2019-20, 82 articles contained at least one Cl-OPE above 1000 mg/kg, with at least one article exceeding this concentration in each waste category examined. By comparison, only 28 samples collected in 2015-16, contained at least one Cl-OPE >1000 mg/kg, and articles exceeding this concentration were restricted to furniture and mattress foam, along with foams and fabrics from end-of-life vehicles. In the event of the introduction of such a limit on Cl-OPE concentrations in waste, it will result in 7200 t/year of such waste (24 % of the total) being rendered unrecyclable, while removing 98 % of the estimated ∼147,000 kg/year of Cl-OPEs from the recycling stream.

Daphnia as a Sentinel Species for Environmental Health Protection: A Perspective on Biomonitoring and Bioremediation of Chemical Pollution.

Despite available technology and the knowledge that chemical pollution damages human and ecosystem health, chemical pollution remains rampant, ineffectively monitored, rarely prevented, and only occasionally mitigated. We present a framework that helps address current major challenges in the monitoring and assessment of chemical pollution by broadening the use of the sentinel species Daphnia as a diagnostic agent of water pollution. And where prevention has failed, we propose the application of Daphnia as a bioremediation agent to help reduce hazards from chemical mixtures in the environment. By applying "omics" technologies to Daphnia exposed to real-world ambient chemical mixtures, we show improvements at detecting bioactive components of chemical mixtures, determining the potential effects of untested chemicals within mixtures, and identifying targets of toxicity. We also show that using Daphnia strains that naturally adapted to chemical pollution as removal agents of ambient chemical mixtures can sustainably improve environmental health protection. Expanding the use of Daphnia beyond its current applications in regulatory toxicology has the potential to improve both the assessment and the remediation of environmental pollution.

POP-BFRs in consumer products: Evolution of the efficacy of XRF screening for legislative compliance over a 5-year interval and future trends.

In 2015-16, a study of approximately 500 waste plastic articles showed that portable X-ray fluorescence (XRF) was up to 95 % effective in screening for compliance with low persistent organic pollutant (POP) concentration limits (LPCLs) on brominated flame retardants (BFRs) in waste. The present study conducted in 2019-20 mirrors that conducted five years prior on a similar number and range of articles, testing the hypothesis that increased use of alternative BFRs as replacements for POP-BFRs will reduce the effectiveness of XRF as a tool for monitoring compliance with LPCLs. In comparing the results, the overall screening efficacy for LPCL compliance reduced from ~95 % to ~88 %, due in part to decreased prevalence of POP-BFRs and potentially increased presence of alternative flame retardants, particularly in goods with shorter lifecycles such as electronics. We additionally examined the impacts of a number of modifications to the XRF measurement protocol on its efficacy, including: using elemental Sb as a qualifier in detecting POP-BFRs in hard plastics; reduced XRF analysis time; and the elimination of background interference using a test stand. The rate at which hard plastics from electronic waste may be analysed by XRF can be substantially improved by reducing analysis time to 5 s, with minimal increase in false exceedances of the LPCL. Monitoring Sb does not appear an effective qualifier for the presence of POP-BFRs, as Sb seems to be used with a range of BFRs. Use of the test stand, while reducing interference, appeared to reduce accuracy when screening low density and thin samples. Despite a seeming increased use of alternative BFRs, screening of waste for compliance with LPCLs using rapid and low-cost screening methods such as portable XRF is still necessary as methods such as GC-MS cannot be scaled up to match the quantities of waste requiring screening.

Halogenated flame retardants in Irish waste polymers: Concentrations, legislative compliance, and preliminary assessment of temporal trends.

Halogenated flame retardants (HFRs) were measured in 470 waste plastic articles from Ireland between 2019 and 2020. We identified articles containing concentrations of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCDD), and tetrabromobisphenol-A (TBBP-A) exceeding European Union limits. Enforcement of existing limits of 1000 mg/kg will render an estimated 3.1% (2800 t) of articles in the waste categories studied unrecyclable, increasing to: 4.0, 4.9, and 5.6% if limits were reduced to 500, 200, and 100 mg/kg respectively. Meanwhile, enforcing limits of 1,000, 500, 200, and 100 mg/kg will respectively remove 78, 82, 84, and 85% of PBDEs, HBCDD, and TBBP-A present in such waste. Other FRs targeted were detected infrequently and predominantly at very low concentrations. However, 2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ) was detected in 3 display/IT product samples at 14,000 to 32,000 mg/kg, indicating elevated concentrations of FRs used as alternatives to PBDEs and HBCDD, will likely increase in future. Comparison with data for Ireland in 2015-16, revealed concentrations and exceedances of limits for PBDEs, HBCDD, and TBBP-A were similar or have declined. For end-of-life vehicle fabrics and foams, HBCDD and ΣPBDE concentrations declined significantly (p < 0.05) since 2015-16. Moreover, ΣPBDE concentrations in waste small domestic appliances are significantly lower in 2019-20, with a similarly significant decline for TBBP-A in waste IT and telecommunications articles. In contrast, HBCDD concentrations in waste extruded polystyrene increased significantly between 2015-16 and 2019-20. For other waste categories studied, no statistically significant temporal trends are evident (p > 0.05). Fewer samples exceeded PBDE and HBCDD limits in 2019-20 (7.8%) than 2015-16 (8.7%), while exceedances for TBBP-A fell from 2.4% in 2015-16 to 0.57% in 2019-20. While comparison between the 2015-16 and 2019-20 datasets provide a preliminary indication of changes, further monitoring is required if the impact of legislation designed to eliminate HFRs from the waste stream is to be fully evaluated.

Concentrations and isomer profiles of hexabromocyclododecanes (HBCDDs) in floor, elevated surface, and outdoor dust samples from Basrah, Iraq.

Concentrations of the α, ß, and γ- diastereomers of hexabromocyclododecane (α-, ß-, and γ-HBCDD) were measured in 60 dust samples from 20 homes across Basrah, Iraq. From each home, two indoor dust (ID) samples (specifically one collected from elevated surfaces (ESD) and one from the floor (FD)) were collected from the living room, with one outdoor dust (OD) sample collected from the front yard of the house. Concentrations of HBCDDs decreased in the following sequence ESD > FD > OD. For ID, ΣHBCDD concentrations varied from 5.3 ng g-1 in FD to 150 ng g-1 in ESD, with median levels of 60 and 40 ng g-1 in ESD and FD respectively. Concentrations of γ-HBCDD, and consequently of ΣHBCDDs in ESD, significantly (p < 0.05) exceeded those in FD. For adults, this implies that exposure assessments based on FD only may underestimate exposure, as adults are more likely to ingest ESD. Concentrations of ΣHBCDDs in OD ranged between 7.4 and 120 ng g-1 with a median of 35 ng g-1 and were significantly exceeded (p < 0.05) by those in ID samples. Concentrations of ΣHBCDDs in OD from houses with car parking areas exceeded (p < 0.05) those in OD from other homes, implying vehicles as potential emission sources of HBCDDs. Simultaneously, there was moderate correlation (R = 0.510-0.609, p < 0.05) between concentrations in ID and OD, implying that the indoor environment is an important source of OD contamination. The isomer pattern of HBCDDs in dust samples displayed a predominance of α-HBCDD, which represented 56%, 52% and 59% ΣHBCDD in ESD, FD and OD samples respectively. Derived from the concentrations reported in this study, the median and 95th percentile estimated daily intakes (EDI) for Iraqi adults and toddlers through house dust ingestion did not exceed the reference dose (RfD) value for HBCDD.

Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown. METHODS: Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1-2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. RESULTS: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks. CONCLUSIONS: In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia. CLINICAL TRIALS REGISTRATION: NCT04363736.

The Time Machine framework: monitoring and prediction of biodiversity loss.

Transdisciplinary solutions are needed to achieve the sustainability of ecosystem services for future generations. We propose a framework to identify the causes of ecosystem function loss and to forecast the future of ecosystem services under different climate and pollution scenarios. The framework (i) applies an artificial intelligence (AI) time-series analysis to identify relationships among environmental change, biodiversity dynamics and ecosystem functions; (ii) validates relationships between loss of biodiversity and environmental change in fabricated ecosystems; and (iii) forecasts the likely future of ecosystem services and their socioeconomic impact under different pollution and climate scenarios. We illustrate the framework by applying it to watersheds, and provide system-level approaches that enable natural capital restoration by associating multidecadal biodiversity changes to chemical pollution.

Formal waste treatment facilities as a source of halogenated flame retardants and organophosphate esters to the environment: A critical review with particular focus on outdoor air and soil.

Extensive use of halogenated flame retardants (HFRs) and organophosphate esters (OPEs) has generated great concern about their adverse effects on environmental and ecological safety and human health. As well as emissions during use of products containing such chemicals, there are mounting concerns over emissions when such products reach the waste stream. Here, we review the available data on contamination with HFRs and OPEs arising from formal waste treatment facilities (including but not limited to e-waste recycling, landfill, and incinerators). Evidence of the transfer of HFRs and OPEs from products to the environment shows that it occurs via mechanisms such as: volatilisation, abrasion, and leaching. Higher contaminant vapour pressure, increased temperature, and elevated concentrations of HFRs and OPEs in products contribute greatly to their emissions to air, with highest emission rates usually observed in the early stages of test chamber experiments. Abrasion of particles and fibres from products is ubiquitous and likely to contribute to elevated FR concentrations in soil. Leaching to aqueous media of brominated FRs (BFRs) is likely to be a second-order process, with elevated dissolved humic matter and temperature of leaching fluids likely to facilitate such emissions. However, leaching characteristics of OPEs are less well-understood and require further investigation. Data on the occurrence of HFRs and OPEs in outdoor air and soil in the vicinity of formal e-waste treatment facilities suggests such facilities exert a considerable impact. Waste dumpsites and landfills constitute a potential source of HFRs and OPEs to soil, and improper management of waste disposal might also contribute to HFR contamination in ambient air. Current evidence suggests minimal impact of waste incineration plants on BFR contamination in outdoor air and soil, but further investigation is required to confirm this.

Atmospheric concentrations of polychlorinated biphenyls, brominated flame retardants, and novel flame retardants in Lagos, Nigeria indicate substantial local sources.

Polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs) like polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCDD), and novel flame retardants (NFRs) like decabromodiphenyl ethane (DBDPE) are ubiquitous environmental pollutants. Despite this, little is known about their concentrations in outdoor air in the African continent. To address this knowledge gap, concentrations of BFRs, NFRs, and PCBs were measured in outdoor air at 8 sites located within the metropolitan area of Lagos, Nigeria. Concentrations of ∑8BDEs, ∑HBCDD, ∑7NFRs and ∑8PCBs were: 21-750 (median = 100) pg/m3, <12-180 (median = < 12) pg/m3, 34-900 (median = 300) pg/m3 and 85-460 (median = 300) pg/m3, respectively. Decabromodiphenyl ether (BDE-209, range: <16-620 pg/m3, median = 71 pg/m3) and DBDPE (range: <37-890 pg/m3, median = 280 pg/m3) were the dominant BFRs detected, while the non-Arochlor PCB 11 (range: 49-220 pg/m3, median = 100 pg/m3) was the dominant PCB. To the authors' knowledge, these are the first data on the non-Arochlor PCB 11 in outdoor air in Africa. In general, concentrations of all target contaminants in this study were within the range reported elsewhere in Africa and worldwide. Likely due to the tropical climate of Lagos, no seasonal variation in concentrations was discernible for any of the target contaminants. While concentrations of PBDEs and some NFRs were correlated with population density, concentrations of PCBs appear more impacted by leaks from electrical transformers and for PCB 11 to proximity to activities like textile factories that produce and use dyes.

Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial.

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.