Phthalate esters: occurrence, toxicity, bioremediation, and advanced oxidation processes.

Phthalic acid esters are emerging pollutants, commonly used as plasticizers that are categorized as hazardous endocrine-disrupting chemicals (EDCs). A rise in anthropogenic activities leads to an increase in phthalate concentration in the environment which leads to various adverse environmental effects and health issues in humans and other aquatic organisms. This paper gives an overview of the research related to phthalate ester contamination and degradation methods by conducting a bibliometric analysis with VOS Viewer. Ecotoxicity analysis requires an understanding of the current status of phthalate pollution, health impacts, exposure routes, and their sources. This review covers five toxic phthalates, occurrences in the aquatic environment, toxicity studies, biodegradation studies, and degradation pathways. It highlights the various advanced oxidation processes like photocatalysis, Fenton processes, ozonation, sonolysis, and modified AOPs used for phthalate removal from the environment.

Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen.

The antioxidant drug ebselen has been widely studied in both laboratories and in clinical trials. The catalytic mechanism by which it destroys hydrogen peroxide via reduction with glutathione or other thiols is complex and has been the subject of considerable debate. During reinvestigations of several key steps, we found that the seleninamide that comprises the first oxidation product of ebselen underwent facile reversible methanolysis to an unstable seleninate ester and two dimeric products. In its reaction with benzyl alcohol, the seleninamide produced a benzyl ester that reacted readily by selenoxide elimination, with formation of benzaldehyde. Oxidation of ebselen seleninic acid did not afford a selenonium seleninate salt as previously observed with benzene seleninic acid, but instead generated a mixture of the seleninic and selenonic acids. Thiolysis of ebselen with benzyl thiol was faster than oxidation by ca. an order of magnitude and produced a stable selenenyl sulfide. When glutathione was employed, the product rapidly disproportionated to glutathione disulfide and ebselen diselenide. Oxidation of the S-benzyl selenenyl sulfide, or thiolysis of the seleninamide with benzyl thiol, afforded a transient thiolseleninate that also readily underwent selenoxide elimination. The S-benzyl derivative disproportionated readily when catalyzed by the simultaneous presence of both the thiol and triethylamine. The phenylthio analogue disproportionated when exposed to ambient or UV (360 nm) light by a proposed radical mechanism. These observations provide additional insight into several reactions and intermediates related to ebselen.

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

Betaine- and L-Carnitine-Based Ionic Liquids as Solubilising and Stabilising Agents for the Formulation of Antimicrobial Eye Drops Containing Diacerein.

The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis. DIA has recently been evaluated as an antimicrobial agent for bacterial keratitis. Two ILs based on natural zwitterionic compounds were investigated: L-carnitine C6 alkyl ester bromide (Carn6), and betaine C6 alkyl ester bromide (Bet6). The stabilising, solubilising, and mucoadhesive properties of ILs were investigated, as well as their cytotoxicity to the murine fibroblast BALB/3T3 clone A31 cell line. Two IL-DIA-based eye drop formulations were prepared, and their efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa was determined. Finally, the eye drops were administered in vivo on New Zealand albino rabbits, testing their tolerability as well as their elimination and degradation kinetics. Both Bet6 and Carn6 have good potential as functional excipients, showing solubilising, stabilising, mucoadhesive, and antimicrobial properties; their in vitro cytotoxicity and in vivo ocular tolerability pave the way for their future use in ophthalmic applications.

Spatiotemporal variations and the ecological risks of organophosphate esters in Laizhou Bay waters between 2019 and 2021: Implying the impacts of the COVID-19 pandemic.

Organophosphate esters (OPEs) are a group of synthetic chemicals used in numerous consumer products such as plastics and furniture. The Coronavirus Disease 2019 (COVID-19) pandemic significantly slowed anthropogenic activities and reduced the emissions of pollutants. Meanwhile, the mismanagement of large quantities of disposable plastic facemasks intensified the problems of plastic pollution and leachable pollutants in coastal waters. In this study, the joint effects of the COVID-19 outbreak on the occurrence of 12 targeted OPEs in the waters of Laizhou Bay (LZB) were investigated. The results showed that the median total OPE concentrations were 725, 363, and 109 ng L-1 in the sewage treatment plant effluent, river water, and bay water in 2021, decreased significantly (p < 0.05) by 67%, 68%, and 70%, respectively, compared with those before the COVID-19 outbreak. The release potential of targeted OPEs from disposable surgical masks in the LZB area was ∼0.24 kg yr-1, which was insufficient to increase the OPE concentration in the LZB waters. The concentrations of most individual OPEs significantly decreased in LZB waters from 2019 to 2021, except for TBOEP and TNBP. Spatially, a lower concentration of OPEs was found in the Yellow River estuary area in 2021 compared with that before the COVID-19 pandemic due to the high content of suspended particulate matter in the YR. A higher total OPE concentration was observed along the northeastern coast of LZB, mainly owing to the construction of an artificial island since 2020. The ecological risks of the OPE mixture in LZB waters were lower than those before the COVID-19 outbreak. However, TCEP, TNBP, and BDP should receive continuous attention because of their potential ecological risks to aquatic organisms.

A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19.

Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an in vitro inhibitory potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical trial in mild to moderate COVID-19 patients. We randomly assigned patients to receive either camostat mesylate (DWJ1248) or placebo orally for 14 days. The primary endpoint was time to clinical improvement of subject symptoms within 14 days, measured using a subjective 4-point Likert scale. Three hundred forty-two patients were randomized. The primary endpoint was nonsignificant, where the median times to clinical improvement were 7 and 8 days in the camostat mesylate group and the placebo group, respectively (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 0.84 to 1.43; P = 0.50). A post hoc analysis showed that the difference was greatest at day 7, without reaching significance. In the high-risk group, the proportions of patients with clinical improvement up to 7 days were 45.8% (50/109) in the camostat group and 38.4% (40/104) in the placebo group (odds ratio [OR] = 1.33; 95% CI, 0.77 to 2.31; P = 0.31); the ordinal scale score at day 7 improved in 20.0% (18/90) of the camostat group and 13.3% (12/90) of the placebo group (OR = 1.68; 95% CI, 0.75 to 3.78; P = 0.21). Adverse events were similar in the two groups. Camostat mesylate was safe in the treatment of COVID-19. Although this study did not show clinical benefit in patients with mild to moderate COVID-19, further clinical studies for high-risk patients are needed. (This trial was registered with ClinicalTrials.gov under registration no. NCT04521296).

Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization (WHO). Since SARS-CoV-2 main protease plays an essential role in the virus's life cycle, the design of small drug molecules with lower molecular weight has been a promising development targeting its inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against SARS-CoV-2 main protease. We employed molecular dynamics (MD) simulations to elucidate the selected compounds' binding free energy profiles against SARS-CoV-2 and further unveil the residues responsible for the drug-binding properties. Compound 8 exhibited the highest binding free energy of -49.37 ± 0.15 kcal/mol, followed by compound 7 (-39.83 ± 0.19 kcal/mol), while compound 17 showed the lowest binding free energy (-23.54 ± 0.19 kcal/mol). In addition, the absorption, distribution, metabolism, and excretion (ADME) assessment was performed and revealed that only compound 17 met the drug-likeness parameters and exhibited high pharmacokinetics to inhibit CYP1A2, CYP2C19, and CYP2C9 with better absorption potential and blood-brain barrier permeability (BBB) index. The additional intermolecular evaluations suggested compound 8 as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound 7 with an aromatic benzene ring in compound 8 significantly enhanced the drug's ability to bind better at the active site of the SARS-CoV-2 Mpro.

Mechanistic investigation of SARS-CoV-2 main protease to accelerate design of covalent inhibitors.

Targeted covalent inhibition represents one possible strategy to block the function of SARS-CoV-2 Main Protease (MPRO), an enzyme that plays a critical role in the replication of the novel SARS-CoV-2. Toward the design of covalent inhibitors, we built a covalent inhibitor dataset using deep learning models followed by high throughput virtual screening of these candidates against MPRO. Two top-ranking inhibitors were selected for mechanistic investigations-one with an activated ester warhead that has a piperazine core and the other with an acrylamide warhead. Specifically, we performed a detailed analysis of the free energetics of covalent inhibition by hybrid quantum mechanics/molecular mechanics simulations. Cleavage of a fragment of the non-structured protein (NSP) from the SARS-CoV-2 genome was also simulated for reference. Simulations show that both candidates form more stable enzyme-inhibitor (E-I) complexes than the chosen NSP. It was found that both the NSP fragment and the activated ester inhibitor react with CYS145 of MPRO in a concerted manner, whereas the acrylamide inhibitor follows a stepwise mechanism. Most importantly, the reversible reaction and the subsequent hydrolysis reaction from E-I complexes are less probable when compared to the reactions with an NSP fragment, showing promise for these candidates to be the base for efficient MPRO inhibitors.

Study protocol of the PROUD48 study comparing the effects of pemafibrate and omega-3 fatty acid ethyl esters on ApoB-48 in statin-treated patients with dyslipidaemia: a prospective, multicentre, open-label, randomised, parallel group trial in Japan.

INTRODUCTION: This study will compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl esters on fasting apolipoprotein B-48 (apoB-48), a surrogate marker reflecting postprandial hypertriglyceridaemia, which is a residual risk for atherosclerotic cardiovascular disease with statin treatment. METHODS AND ANALYSIS: This is a prospective, multicentre, open-label, randomised, parallel group, comparative trial. Adult Japanese patients with dyslipidaemia receiving statin treatment for more than 4 weeks with a fasting triglyceride level ≥177 mg/dL will be randomly assigned in a 1:1 ratio to receive pemafibrate (0.4 mg orally per day) or omega-3 fatty acid ethyl esters (4 g orally per day) for 16 weeks. The primary endpoint is the percentage change in fasting apoB-48 from baseline to 16 weeks. The key secondary endpoints include the change in fasting apoB-48 from baseline to 16 weeks, the percentage changes in clinical variables from baseline to 16 weeks and the incidence of adverse events. A total sample size of 128 was set by considering the increased drop-out rate due to the COVID-19 pandemic, in addition to estimation based on a two-sided alpha of 0.05 and a power of 0.8 for apoB-48. ETHICS AND DISSEMINATION: The study protocol has been approved by the Certified Review Board of the University of the Ryukyus for Clinical Research Ethics (No. CRB7200001) and will be performed in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants. The results of the study will be disseminated through publications and conference presentations to participants, healthcare professionals and the public. TRIAL REGISTRATION NUMBER: jRCTs071200011.

Dynamic variation and inhalation exposure of organophosphates esters and phthalic acid esters in face masks.

The coronavirus pandemic (COVID-19) has posed a huge global health threat since December 2019. Wearing face masks is known as an effective measure for controlling the wide spread of COVID-19 and its variants. But on the other hand, face masks could be a potential source of organophosphate esters (OPEs) and phthalic acid esters (PAEs) as they are extensively added in masks. However, knowledge associated with the occurrence as well as inhalation risks of OPEs and PAEs in masks is limited. In this study, OPEs and PAEs were determined in different types of mask samples collected from the local market. OPEs and PAEs were detected in mask samples ranging from 36.7 to 855 ng/g, and from 251 to 3830 ng/g, respectively. Relatively lower OPEs and PAEs concentrations were observed in disposable mask for toddlers. Simulated inhalation experiment indicated that the mass loss of OPEs and PAEs was 136 and 3910 ng/mask in disposable masks, 71.9 and 763 ng/mask in disposable mask for toddlers, 924 and 1020 ng/mask in N95 mask after 12 h, respectively. Significantly negative correlations were exhibited between the decrement of OPEs in masks and the increment of OPEs in corresponding polyurethane foams (PUFs) during the course, elucidating OPEs released from masks could be well captured by PUFs. With regard to the variation over time, predominant OPE and PAE analogues showed semblable release and absorption tendency in mask and corresponding PUF. Inhalation exposure risk of OPEs and PAEs was estimated based on the increment of pollutants in PUF. The estimated daily intakes (EDIs), hazard index (HI) and carcinogenic risk (CR) were also calculated and they were within the threshold levels. This study provides the evidence of OPEs and PAEs releasing from the face masks during wearing and unveiled a potential source of OPEs and PAEs exposure to humans.

Exploring new catechin derivatives as SARS-CoV-2 Mpro inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations.

SARS-CoV-2 Mpro (Mpro) is the critical cysteine protease in coronavirus viral replication. Tea polyphenols are effective Mpro inhibitors. Therefore, we aim to isolate and synthesize more novel tea polyphenols from Zhenghedabai (ZHDB) white tea methanol-water (MW) extracts that might inhibit COVID-19. Through molecular networking, 33 compounds were identified and divided into 5 clusters. Further, natural products molecular network (MN) analysis showed that MN1 has new phenylpropanoid-substituted ester-catechin (PSEC), and MN5 has the important basic compound type hydroxycinnamoylcatechins (HCCs). Thus, a new PSEC (1, PSEC636) was isolated, which can be further detected in 14 green tea samples. A series of HCCs were synthesized (2-6), including three new acetylated HCCs (3-5). Then we used surface plasmon resonance (SPR) to analyze the equilibrium dissociation constants (KD) for the interaction of 12 catechins and Mpro. The KD values of PSEC636 (1), EGC-C (2), and EC-CDA (3) were 2.25, 2.81, and 2.44 µM, respectively. Moreover, compounds 1, 2, and 3 showed the potential Mpro inhibition with IC50 5.95 ± 0.17, 9.09 ± 0.22, and 23.10 ± 0.69 µM, respectively. Further, we used induced fit docking (IFD), binding pose metadynamics (BPMD), and molecular dynamics (MD) to explore the stable binding pose of Mpro-1, showing that 1 could tightly bond with the amino acid residues THR26, HIS41, CYS44, TYR54, GLU166, and ASP187. The computer modeling studies reveal that the ester, acetyl, and pyrogallol groups could improve inhibitory activity. Our research suggests that these catechins are effective Mpro inhibitors, and might be developed as therapeutics against COVID-19.

Plasmonic photonic biosensor: in situ detection and quantification of SARS-CoV-2 particles.

We conceptualized and numerically investigated a photonic crystal fiber (PCF)-based surface plasmon resonance (SPR) sensor for rapid detection and quantification of novel coronavirus. The plasmonic gold-based optical sensor permits three different ways to quantify the virus concentrations inside patient's body based on different ligand-analyte conjugate pairs. This photonic biosensor demonstrates viable detections of SARS-CoV-2 spike receptor-binding-domain (RBD), mutated viral single-stranded ribonucleic acid (RNA) and human monoclonal antibody immunoglobulin G (IgG). A marquise-shaped core is introduced to facilitate efficient light-tailoring. Analytes are dissolved in sterile phosphate buffered saline (PBS) and surfaced on the plasmonic metal layer for realizing detection. The 1-pyrene butyric acid n-hydroxy-succinimide ester is numerically used to immobilize the analytes on the sensing interface. Using the finite element method (FEM), the proposed sensor is studied critically and optimized for the refractive index (RI) range from 1.3348-1.3576, since the target analytes RIs fluctuate within this range depending on the severity of the viral infection. The polarization-dependent sensor exhibits dominant sensing attributes for x-polarized mode, where it shows the average wavelength sensitivities of 2,009 nm/RIU, 2,745 nm/RIU and 1,984 nm/RIU for analytes: spike RBD, extracted coronavirus RNA and antibody IgG, respectively. The corresponding median amplitude sensitivities are 135 RIU-1, 196 RIU-1 and 140 RIU-1, respectively. The maximum sensor resolution and figure of merit are found 2.53 × 10-5 RIU and 101 RIU-1, respectively for viral RNA detection. Also, a significant limit of detection (LOD) of 6.42 × 10-9 RIU2/nm is obtained. Considering modern bioassays, the proposed compact photonic sensor will be well-suited for rapid point-of-care COVID testing.

Determination and risk assessment of phthalates in face masks. An Italian study.

Serious human health concerns have been recently raised from daily use of face masks, due to the possible presence of hazardous compounds as the phthalic acid esters (PAEs). In this study, the content of 11 PAEs in 35 commercial masks was assessed by applying a specific and accurate method, using Gas Chromatography/Mass Spectrometry. Surgical, FFP2 and non-surgical models, for both adults and children were collected from the Italian market. Analyses showed that four of the target analytes were detected in all tested samples with median total concentrations ranging between 23.6 mg/kg and 54.3 mg/kg. Results obtained from the experimental analysis were used in the risk assessment studies carried out for both carcinogenic and non-carcinogenic effects. Doses of exposure (Dexp) of PAEs ranged from 6.43 × 10-5 mg/kg bw/day to 1.43 × 10-2 mg/kg bw/day. Cumulative risk assessment was performed for non-carcinogenic and carcinogenic effects. No potential risk was found for non-carcinogenic effects, yet the 20% of the mask samples showed potential carcinogenic effects for humans. A refined exposure assessment was performed showing no risk for carcinogenic effects. This paper presents a risk assessment approach for the identification of potential risks associated to the use of face masks.

Colorimetric Detection of the SARS-CoV-2 Virus (COVID-19) in Artificial Saliva Using Polydiacetylene Paper Strips.

The spread and resurgence of the SARS-CoV-2 virus (COVID-19 disease) threatens human health and social relations. Prevention of COVID-19 disease partly relies on fabricating low-cost, point-of-care (POC) sensing technology that can rapidly and selectively detect the SARS-CoV-2 virus. We report a colorimetric, paper-based polydiacetylene (PDA) biosensor, designed to detect SARS-CoV-2 spike protein in artificial saliva. Analytical characterizations of the PDA sensor using NMR and FT-IR spectroscopy showed the correct structural elucidation of PCDA-NHS conjugation. The PDA sensor platform containing the N-Hydroxysuccinimide ester of 10, 12-pentacosadiynoic acid (PCDA-NHS) was divided into three experimental PCDA-NHS concentration groups of 10%, 20%, and 30% to optimize the performance of the sensor. The optimal PCDA-NHS molar concentration was determined to be 10%. The PDA sensor works by a color change from blue to red as its colorimetric output when the immobilized antibody binds to the SARS-CoV-2 spike protein in saliva samples. Our results showed that the PDA sensing platform was able to rapidly and qualitatively detect the SARS-CoV-2 spike protein within the concentration range of 1 to 100 ng/mL after four hours of incubation. Further investigation of pH and temperature showed minimal influence on the PDA sensor for the detection of COVID-19 disease. After exposure to the SARS-CoV-2 spike protein, smartphone images of the PDA sensor were used to assess the sensor output by using the red chromatic shift (RCS) of the signal response. These results indicate the potential and practical use of this PDA sensor design for the rapid, colorimetric detection of COVID-19 disease in developing countries with limited access to medical testing.

Cyclic Phthalate Esters as Liver X Receptor Antagonists with Anti-hepatitis C Virus and Anti-severe Acute Respiratory Syndrome Coronavirus 2 Properties.

The liver X receptor is a nuclear hormone receptor that regulates lipid metabolism. Previously, we had demonstrated the antiviral properties of a liver X receptor antagonist associated with the hepatitis C virus and severe acute respiratory syndrome coronavirus 2. In this study, we screened a chemical library and identified two potential liver X receptor antagonists. Spectroscopic analysis revealed that the structures of both antagonists (compounds 1 and 2) were cyclic dimer and trimer of esters, respectively, that consisted of phthalate and 1,6-hexane diol. This study is the first to report the structure of the cyclic trimer of phthalate ester. Further experiments revealed that the compounds were impurities of solvents used for purification, although their source could not be traced. Both phthalate esters exhibited anti-hepatitis C virus activity, whereas the cyclic dimer showed anti-severe acute respiratory syndrome coronavirus 2 activity. Cyclic phthalate derivatives may constitute a novel class of liver X receptor antagonists and broad-spectrum antivirals.

A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study).

BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

Release of phthalate esters (PAEs) and microplastics (MPs) from face masks and gloves during the COVID-19 pandemic.

Marine pollution with personal protective equipment (PPE) has recently gained major attention. Multiple studies reported the release of microplastics (MPs) and chemical contaminants from face masks, the most used PPE type. However, not much is known concerning the release of phthalate esters (PAEs) in aquatic media, as well as the hazard posed by other types of PPE. In the present study, we investigated the release of MPs and PAEs from face masks and gloves recovered from the environment. The results indicated that both PPEs release MPs comparable to the literature, but higher concentrations were presented by face masks. In turn, the total concentration of six PAEs was higher in gloves than in face masks. The release of these contaminants is exacerbated over time. The present study allows researchers to understand the contribution of PPE to marine pollution while accounting for gloves, a generally overlooked source of contaminants.

EsteR - A Digital Toolkit for COVID-19 Decision Support in Local Health Authorities.

In Germany, the current COVID-19 cases are managed and reported by the local health authorities. The workload of their employees during the pandemic is high, especially in periods of high infection numbers. In this work a decision support toolkit for local health authorities is introduced. A demonstrator web application was developed with the R Shiny framework and is publicly accessible online. It contains five separate tools based on statistical models for specific use cases and corresponding questions of COVID-19 cases and their contacts. The underlying statistical methods have been implemented in a new open-source R package. The toolkit has the potential to support local health authorities' employees in their daily work. A simulated-based validation of the statistical models and a usability evaluation of the demonstrator application in a user study will be carried out in the future.

New type of RNA virus replication inhibitor based on decahydro-closo-decaborate anion containing amino acid ester pendant group.

In this work, a synthetic approach to prepare an example of new class of the derivatives of the closo-decaborate anion with amino acids detached from the boron cluster by pendant group has been proposed and implemented. Compound Na2[B10H9-O(CH2)4C(O)-His-OMe] was isolated and characterized. This compound has an inorganic hydrophobic core which is the 10-vertex boron cage and the -O(CH2)4C(O)-His-OMe organic substituent. It has been shown to possess strong antiviral activity in vitro against modern strains of A/H1N1 virus at 10 and 5 µg/mL. The compound has been found to be non-cytotoxic up to 160 µg/mL. At the same time, the compound has been found to be inactive against SARS-CoV-2, indicating specific activity against RNA virus replication. Molecular docking of the target derivative of the closo-decaborate anion with a model of the transmembrane region of the M2 protein has been performed and the mechanism of its antiviral action is discussed.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.