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The metabolic functionality of the gut microbiota contributes to the metabolism and well-being of its host, although detailed insight in the microbiota's metabolism is lacking. Omics technologies could facilitate unraveling metabolism by the gut microbiota. In this study, we performed metabolite profiling of different matrices of the gut, after antibiotic treatment of rats in order to evaluate metabolite changes observed at different dose levels and in different sexes, and to identify the best tissue matrix for further investigations regarding an assessment of metabolic effects of new compounds with antibiotic activity. Three different antibiotics (vancomycin, streptomycin and roxithromycin) were administered orally to rats for 28 days according to the OECD 407 guideline with a subsequent metabolic profiling in feces, cecum content and gut tissue (jejunum, ileum, cecum, colon and rectum). The data were analyzed in the MetaMap®Tox database. Treatment-related effects could be observed in the metabolite profile of feces and cecum content, but not of the different gut tissues. The metabolite profile showed compound specific effects on the microbiome. In line with the activity spectra of the antibiotics tested, vancomycin showed the largest effects, followed by roxithromycin and then by streptomycin for which changes were modest. In general, for all antibiotics the largest changes were observed for the classes of lipids (increase up to 94-fold), bile acids (increase up to 33-fold), amino acids (increase up to 200-fold) and amino acid related (increase up to 348-fold). The most relevant changes in metabolite values were similar in feces and cecum content and among sexes. The results of this targeted analysis indicate that the metabolic profiles of male and female animals in the gut microbiome are comparable. Concluding, taking other samples than feces does not add any extra information. Thus, as a non-invasive sampling method, feces provide a suitable matrix for studies on metabolism by the gut microbiota. [ABSTRACT FROM AUTHOR]

Describes a right-handed patient with a mild cognitive deterioration who demonstrated the neuropsychological deficits of progressive bi-temporal atrophy. Process of familiar person recognition and identification; Testing with unfamiliar and famous faces; Informal face recognition testing with photographs of the patient's family.

Objective: To determine whether naproxen, a propionic acid inhibitor of cyclooxygenase, alters the course of experimental rhinovirus colds.Design: A randomized, double-blind, controlled trial.Setting: Rhinovirus challenge model in volunteers cloistered in individual hotel rooms.Volunteers: Eighty-seven healthy young adults with serum neutralizing antibody titers of less than or equal to 1:2 to the challenge virus; 79 were evaluable.Intervention: Thirty-nine participants received naproxen (loading dose, 400 mg or 500 mg followed by 200 mg or 500 mg three times daily for 5 days). Forty participants received placebo. Treatment was started 6 hours after viral challenge.Measurements: Daily measurement of viral titers, symptoms, nasal mucus production, and nasal tissue use; incidence of infection and illness; and measurement of homotypic serum neutralizing antibody responses.Results: Viral titers and serum homotypic antibody responses were similar in the naproxen and placebo groups. Significant reductions in headache, malaise, myalgia, and cough occurred in the naproxen group. A 29% reduction was noted in the total (5-day) symptom score in the naproxen group (95% CI, 16% to 42%).Conclusion: Naproxen treatment did not alter virus shedding or serum neutralizing antibody responses in participants with experimental rhinovirus colds, but it had a beneficial effect on the symptoms of headache, malaise, myalgia, and cough. Prostaglandins may be among the inflammatory mediators that play a role in the pathogenesis of rhinovirus colds. [ABSTRACT FROM AUTHOR]

Highlights • Metabolomics is a useful tool for a mechanism-based identification of rat maternal toxicity. • The metabolome-derived NOEL was more sensitive in detecting maternal toxicity than the maternal NOAEL. • Specific metabolome patterns were established in pregnant rats. Abstract For regulatory purposes prenatal developmental toxicity (OECD No. 414) studies are routinely performed in our laboratories. The suitability of metabolomics as technology to identify maternal toxicity in such studies was investigated. Plasma was sampled from pregnant, non-fasted rats on gestation day 20 before cesarean section. Metabolite profiling was performed by gas- and liquid-chromatography-tandem mass spectrometry techniques. The sensitivity of routinely examined maternal toxicity parameters (OECD No. 414) was compared to those of metabolome analysis. Evaluating 44 studies, the metabolome-derived NOEL was more sensitive in 45% of the cases in detecting maternal toxicity than the maternal NOAEL. Metabolome patterns indicative for liver effects and 4-hydroxyphenylpyruvate dioxygenase (HPPD) enzyme-inhibition were established in pregnant rats based on regulated metabolites using reference compounds. The HPPD inhibition and liver toxicity patterns in pregnant rats were reasonably comparable to the ones established in non-pregnant, fasted rats. Metabolomics is a useful tool for an improved and mechanism-based identification of maternal toxicity in maternal and prenatal toxicity studies. The data suggest that the current classical maternal toxicity parameters may underestimate the extent of effects of compounds on the dams. [ABSTRACT FROM AUTHOR]

Abstract The bile acid-liver-gut microbiota axis plays an important role in the host's health. The gut microbiota has an impact on the bile acid pool, but also the bile acids themselves can influence the gut microbiota composition. In this study, six antibiotics from five different classes (i.e. lincosamides, glycopeptides, macrolides, fluoroquinolones, aminoglycosides) were used to modulate microbial communities of Wistar rats to elucidate changes in the bile acid metabolism and to identify key metabolites in the bile acid pool related to gut microbial changes. 20 primary and secondary bile acids were analyzed in plasma and feces of control and treated animals. Antibiotics treatment induced significant changes in primary and secondary bile acids in both matrices. Taurine-conjugated primary bile acids significantly increased in plasma and feces. Contrary, cholic acid and most of the analyzed secondary bile acids significantly decreased in plasma, and cholic acid accumulated in the feces after treatment with all antibiotics but roxithromycin. Despite the different activity spectra of the antibiotics applied against gut microbes, the overall effect on the bile acid pool tended to be similar in both matrices except for streptomycin. These results show that changes in the gut microbial community affect the bile acid pool in plasma and feces and that changes in the bile acid profile can be indicative of alterations of the gut microbiome. Due to the important role of bile acids for the host, changes in the bile acid pool can have severe consequences for the host. Highlights • Antibiotics induced significant changes in primary and secondary bile acids. • Changes in the gut microbiome affect the bile acid pool in plasma and feces. • Taurine-conjugated primary bile acids significantly increased in plasma and feces. • Cholic acid and most of the analyzed secondary bile acids significantly decreased. [ABSTRACT FROM AUTHOR]

A 14-day rat study with plasma metabolomics was conducted to evaluate the toxicity of Benzene. Wistar rats were orally administered Benzene daily at doses of 0, 300 and 1000 mg/kg bw. The study identified liver and kidneys as target organs of Benzene toxicity and found reductions in total white blood cells, absolute lymphocyte and eosinophil cell counts, and increased relative monocyte counts suggesting bone marrow as a target organ. The study also confirmed liver as a target organ using metabolomics, which showed indications of a stress reaction in rats and changes in metabolites suggestive of a metabolic disorder. The metabolomics investigations did not find any other toxicologically relevant modes of action, and the observed metabolite changes were not associated with markers for mitochondrial dysfunction. The study concludes that integration of omics technologies, such as metabolomics, in regulatory toxicity studies is possible, confirms existing knowledge and adds additional information that can be used for mechanistic understanding of observed toxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Frank Faulhammer: is employed by BASF including stock ownership Bennard van Ravenzwaay: declares to have no known financial or personal relationships that could have appeared to influence the work reported in this paper A. Robert Schnatter: declares to have no known financial or personal relationships that could have appeared to influence the work reported in this paper Martijn Rooseboom: is employed by Shell including stock ownership Hennicke Kamp: is managing director of BASF Metabolome Solutions, a company that is offering metabolome analysis for various applications including toxicology research to external clients and BASF. He is employed by BASF including stock ownership Burkhard Flick: declares to have no known financial or personal relationships that could have appeared to influence the work reported in this paper Varun Giri: is employed by BASF including stock ownership Saskia Sperber: is employed by BASF including stock ownership Larry G Higgins and Michael G Penman: Penman Consulting provide consultancy services to the LOA REACH Consortium, and this article reflects the positions developed in the course of this work Neslihan Aygun Kocabas: is employed by TotalEnergies including stock ownership., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

(1) Background: The rise in electronic cigarette (E-cigarette) popularity, especially among adolescents, has prompted research to investigate potential effects on health. Although much research has been carried out on the effect on lung health, the first site exposed to vaping-the oral cavity-has received relatively little attention. The aims of this study were twofold: to examine the effects of E-liquids on the viability and hydrophobicity of oral commensal streptococci, and the effects of E-cigarette-generated aerosols on the biomass and viability of oral commensal streptococci. (2) Methods: Quantitative and confocal biofilm analysis, live-dead staining, and hydrophobicity assays were used to determine the effect on oral commensal streptococci after exposure to E-liquids and/or E-cigarette-generated aerosols. (3) Results: E-liquids and flavors have a bactericidal effect on multispecies oral commensal biofilms and increase the hydrophobicity of oral commensal streptococci. Flavorless and some flavored E-liquid aerosols have a bactericidal effect on oral commensal biofilms while having no effect on overall biomass. (4) Conclusions: These results indicate that E-liquids/E-cigarette-generated aerosols alter the chemical interactions and viability of oral commensal streptococci. Consequently, the use of E-cigarettes has the potential to alter the status of disease and health in the oral cavity and, by extension, affect systemic health.

Dicyclopentadiene (DCPD) was investigated in a 14-day oral rat toxicity study based on the OECD 407 guideline in combination with plasma metabolomics. Wistar rats received the compound daily via gavage at dose levels of 0, 50 and 150 mg/kg bw. The high dose induced transient clinical signs of toxicity and in males only reduced body weight gain. High dose liver changes were characterized by altered clinical chemistry parameters in both sexes and pathological changes in females. In high dose males an accumulation of alpha-2 u-globulin in the kidney was noted. Comparing the DCPD metabolome with previously established specific metabolome patterns in the MetaMap® Tox data base suggested that the high dose would result in liver enzyme induction leading to increased breakdown of thyroid hormones for males and females. An indication for liver toxicity in males was also noted. Metabolomics also suggested an effect on the functionality of the adrenals in high dose males, which together with published data, is suggestive of a stress related effect in this organ. The results of the present 14-day combined toxicity and metabolome investigations were qualitatively in line with literature data from subchronic oral studies in rats with DCPD. Importantly no other types of organ toxicity, or hormone dysregulation beyond the ones associated with liver enzyme induction and stress were indicated, again in line with results of published 90-day studies. It is therefore suggested that short term "smart" studies, combining classical toxicity with 'omics technologies, could be a 2 R (refine and reduce) new approach method allowing for the reduction of in vivo toxicity testing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

There is currently no suitable autologous tissue to bridge large tracheal defects. As a result, no standard of care exists for long-segment tracheal reconstruction. Tissue engineering has the potential to create a scaffold from allografts or xenografts that can support neotissue regeneration identical to the native trachea. Recent advances in tissue engineering have led to the idea of partial decellularization that allows for the creation of tracheal scaffolds that supports tracheal epithelial formation while preserving mechanical properties. However, the ability of partial decellularization to eliminate graft immunogenicity remains unknown, and understanding the immunogenic properties of partially decellularized tracheal grafts (PDTG) is a critical step toward clinical translation. Here, we determined that tracheal allograft immunogenicity results in epithelial cell sloughing and replacement with dysplastic columnar epithelium and that partial decellularization creates grafts that are able to support an epithelium without histologic signs of rejection. Moreover, allograft implantation elicits CD8+ T-cell infiltration, a mediator of rejection, while PDTG did not. Hence, we establish that partial decellularization eliminates allograft immunogenicity while creating a scaffold for implantation that can support spatially appropriate airway regeneration., Competing Interests: The authors have no conflicts of interest to disclose as described by the American Journal of Transplantation., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.)

The diversity of microbial species in the gut has a strong influence on health and development of the host. Further, there are indications that the variation in expression of gut bacterial metabolic enzymes is less diverse than the taxonomic profile, underlying the importance of microbiome functionality, particularly from a toxicological perspective. To address these relationships, the gut bacterial composition of Wistar rats was altered by a 28 day oral treatment with the antibiotics tobramycin or colistin sulfate. On the basis of 16S marker gene sequencing data, tobramycin was found to cause a strong reduction in the diversity and relative abundance of the microbiome, whereas colistin sulfate had only a marginal impact. Associated plasma and fecal metabolomes were characterized by targeted mass spectrometry-based profiling. The fecal metabolome of tobramycin-treated animals had a high number of significant alterations in metabolite levels compared to controls, particularly in amino acids, lipids, bile acids (BAs), carbohydrates, and energy metabolites. The accumulation of primary BAs and significant reduction of secondary BAs in the feces indicated that the microbial alterations induced by tobramycin inhibit bacterial deconjugation reactions. The plasma metabolome showed less, but still many alterations in the same metabolite groups, including reductions in indole derivatives and hippuric acid, and furthermore, despite marginal effects of colistin sulfate treatment, there were nonetheless systemic alterations also in BAs. Aside from these treatment-based differences, we also uncovered interindividual differences particularly centering on the loss of Verrucomicrobiaceae in the microbiome, but with no apparent associated metabolite alterations. Finally, by comparing the data set from this study with metabolome alterations in the MetaMapTox database, key metabolite alterations were identified as plasma biomarkers indicative of altered gut microbiomes resulting from a wide activity spectrum of antibiotics.

An understanding of the changes in gut microbiome composition and its associated metabolic functions is important to assess the potential implications thereof on host health. Thus, to elucidate the connection between the gut microbiome and the fecal and plasma metabolomes, two poorly bioavailable carbapenem antibiotics (doripenem and meropenem), were administered in a 28-day oral study to male and female Wistar rats. Additionally, the recovery of the gut microbiome and metabolomes in doripenem-exposed rats were studied one and two weeks after antibiotic treatment (i.e., doripenem-recovery groups). The 16S bacterial community analysis revealed an altered microbial population in all antibiotic treatments and a recovery of bacterial diversity in the doripenem-recovery groups. A similar pattern was observed in the fecal metabolomes of treated animals. In the recovery group, particularly after one week, an over-compensation was observed in fecal metabolites, as they were significantly changed in the opposite direction compared to previously changed metabolites upon 28 days of antibiotic exposure. Key plasma metabolites known to be diagnostic of antibiotic-induced microbial shifts, including indole derivatives, hippuric acid, and bile acids were also affected by the two carbapenems. Moreover, a unique increase in the levels of indole-3-acetic acid in plasma following meropenem treatment was observed. As was observed for the fecal metabolome, an overcompensation of plasma metabolites was observed in the recovery group. The data from this study provides insights into the connectivity of the microbiome and fecal and plasma metabolomes and demonstrates restoration post-antibiotic treatment not only for the microbiome but also for the metabolomes. The importance of overcompensation reactions for health needs further studies.

To elucidate if artificial sweeteners modify fecal bacterial composition and the fecal and plasma metabolomes, Wistar rats from both sexes were treated for 28 days with acesulfame potassium (40 and 120 mg/kg body weight) and saccharin (20 and 100 mg/kg body weight). Targeted MS-based metabolome profiling (plasma and feces) and fecal 16S gene sequencing were conducted. Both sweeteners exhibited only minor effects on the fecal metabolome and microbiota. Saccharin treatment significantly altered amino acids, lipids, energy metabolism and specifically, bile acids in the plasma metabolome. Additionally, sex-specific differences were observed for conjugated primary and secondary bile acids. Acesulfame potassium treated male rats showed larger alterations in glycine conjugated primary and secondary bile-acids than females. Other changes in the plasma metabolome were more profound for saccharin than acesulfame potassium, for both sexes. Changes in conjugated bile-acids in plasma, which are often associated with microbiome changes, and the absence of similarly large changes in microbiota suggest an adaptative change of the latter, rather than toxicity. Further studies with a high resolution 16S sequencing data and/or metagenomics approach, with particular emphasis on bile acids, will be required to explore the mechanisms driving this metabolic outcome of saccharin in Wistar rats., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The oral uptake of nanoparticles is an important route of human exposure and requires solid models for hazard assessment. While the systemic availability is generally low, ingestion may not only affect gastrointestinal tissues but also intestinal microbes. The gut microbiota contributes essentially to human health, whereas gut microbial dysbiosis is known to promote several intestinal and extra-intestinal diseases. Gut microbiota-derived metabolites, which are found in the blood stream, serve as key molecular mediators of host metabolism and immunity., Results: Gut microbiota and the plasma metabolome were analyzed in male Wistar rats receiving either SiO 2 (1000 mg/kg body weight/day) or Ag nanoparticles (100 mg/kg body weight/day) during a 28-day oral gavage study. Comprehensive clinical, histopathological and hematological examinations showed no signs of nanoparticle-induced toxicity. In contrast, the gut microbiota was affected by both nanoparticles, with significant alterations at all analyzed taxonomical levels. Treatments with each of the nanoparticles led to an increased abundance of Prevotellaceae, a family with gut species known to be correlated with intestinal inflammation. Only in Ag nanoparticle-exposed animals, Akkermansia, a genus known for its protective impact on the intestinal barrier was depleted to hardly detectable levels. In SiO 2 nanoparticles-treated animals, several genera were significantly reduced, including probiotics such as Enterococcus. From the analysis of 231 plasma metabolites, we found 18 metabolites to be significantly altered in Ag-or SiO 2 nanoparticles-treated rats. For most of these metabolites, an association with gut microbiota has been reported previously. Strikingly, both nanoparticle-treatments led to a significant reduction of gut microbiota-derived indole-3-acetic acid in plasma. This ligand of the arylhydrocarbon receptor is critical for regulating immunity, stem cell maintenance, cellular differentiation and xenobiotic-metabolizing enzymes., Conclusions: The combined profiling of intestinal microbiome and plasma metabolome may serve as an early and sensitive indicator of gut microbiome changes induced by orally administered nanoparticles; this will help to recognize potential adverse effects of these changes to the host., (© 2022. The Author(s).)

Perceptual adaptation is often studied within a single sense. However, our experience of the world is naturally multisensory. Here, we investigated cross-sensory (visual-vestibular) adaptation of self-motion perception. It was previously found that relatively long visual self-motion stimuli (≳15 sec) are required to adapt subsequent vestibular perception, and that shorter duration stimuli do not elicit cross-sensory (visual↔vestibular) adaptation. However, it is not known whether several discrete short-duration stimuli may lead to cross-sensory adaptation (even when their sum, if presented together, would be too short to elicit cross-sensory adaptation). This would suggest that the brain monitors and adapts to supra-modal statistics of events in the environment. Here we investigated whether cross-sensory (visual↔vestibular) adaptation occurs after experiencing several short (1 sec) self-motion stimuli. Forty-five participants discriminated the headings of a series of self-motion stimuli. To expose adaptation effects, the trials were grouped in 140 batches, each comprising three 'prior' trials, with headings biased to the right or left, followed by a single unbiased 'test' trial. Right, and left-biased batches were interleaved pseudo-randomly. We found significant adaptation in both cross-sensory conditions (visual prior and vestibular test trials, and vice versa), as well as both unisensory conditions (when prior and test trials were of the same modality - either visual or vestibular). Fitting the data with a logistic regression model revealed that adaptation was elicited by the prior stimuli (not prior choices). These results suggest that the brain monitors supra-modal statistics of events in the environment, even for short-duration stimuli, leading to functional (supra-modal) adaptation of perception., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We describe a strategy using an in vitro metabolomics assay with tubular rat NRK-52E cells to investigate the Modes of Action (MoAs) of nephrotoxic compounds. Chemicals were selected according to their MoAs based on literature information: acetaminophen, 4-aminophenol and S-(trichlorovinyl-)L-cysteine (TCVC), (covalent protein binding); gentamycin, vancomycin, polymycin B and CdCl 2 (lysosomal overload) and tenofovir and cidofovir (mitochondrial DNA-interaction). After treatment and harvesting of the cells, intracellular endogenous metabolites were quantified relative to vehicle control. Metabolite patterns were evaluated in a purely data-driven pattern generation process excluding published information. This strategy confirmed the assignment of the chemicals to the respective MoA except for TCVC and CdCl 2 . Finally, TCVC was defined as unidentified and CdCl 2 was reclassified to the MoA "covalent protein binding". Hierarchical cluster analysis of 58 distinct metabolites from the patterns enabled a clear visual separation of chemicals in each MoA. The assay reproducibility was very good and metabolic responses were consistent. These results support the use of metabolome analysis in NRK-52E cells as a suitable tool for understanding and investigating the MoA of nephrotoxicants. This assay could enable the early identification of nephrotoxic compounds and finally reduce animal testing., Competing Interests: Declaration of Competing Interest BASF SE might use this approach also in the future for registration of their products., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) manifests sensory and perceptual atypicalities. Recent theories suggest that these may reflect a reduced influence of prior information in ASD. Some studies have found reduced adaptation to recent sensory stimuli in ASD. However, the effects of prior stimuli and prior perceptual choices can counteract one-another. Here, we investigated this using two different tasks (in two different cohorts): (i) visual location discrimination and (ii) multisensory (visual-vestibular) heading discrimination. We fit the data using a logistic regression model to dissociate the specific effects of prior stimuli and prior choices. In both tasks, perceptual decisions were biased toward recent choices. Notably, the 'attractive' effect of prior choices was significantly larger in ASD (in both tasks and cohorts), while there was no difference in the influence of prior stimuli. These results challenge theories of reduced priors in ASD, and rather suggest an increased consistency bias for perceptual decisions in ASD., Competing Interests: HF, SS, DZ, AZ No competing interests declared, (© 2021, Feigin et al.)

Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.

Hydroxychloroquine has been touted as a potential COVID-19 treatment. Tocilizumab, an inhibitor of IL-6, has also been proposed as a treatment of critically ill patients. In this retrospective observational cohort study drawn from electronic health records we sought to describe the association between mortality and hydroxychloroquine or tocilizumab therapy among hospitalized COVID-19 patients. Patients were hospitalized at a 13-hospital network spanning New Jersey USA between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2. Follow up was through May 5, 2020. Among 2512 hospitalized patients with COVID-19 there have been 547 deaths (22%), 1539 (61%) discharges and 426 (17%) remain hospitalized. 1914 (76%) received at least one dose of hydroxychloroquine and 1473 (59%) received hydroxychloroquine with azithromycin. After adjusting for imbalances via propensity modeling, compared to receiving neither drug, there were no significant differences in associated mortality for patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality for patients receiving hydroxychloroquine alone, azithromycin alone, the combination or neither drug was 25%, 20%, 18%, and 20%, respectively. Among 547 evaluable ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend towards an improved survival association with tocilizumab treatment (adjusted HR, 0.76 [95% CI, 0.57-1.00]), with 30 day unadjusted mortality with and without tocilizumab of 46% versus 56%. This observational cohort study suggests hydroxychloroquine, either alone or in combination with azithromycin, was not associated with a survival benefit among hospitalized COVID-19 patients. Tocilizumab demonstrated a trend association towards reduced mortality among ICU patients. Our findings are limited to hospitalized patients and must be interpreted with caution while awaiting results of randomized trials. Trial Registration: Clinicaltrials.gov Identifier: NCT04347993., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DAB, SMB, and NSB are employed by Berry Consultants LLC which provided statistical support for the study. EH, AHG, ALP, SM, and SLG are employed or have ownership interest in COTA Inc which provided statistical support for the study. AHG discloses consulting fees from Physicians’ Education Resource, LLC for his contributions to COVID-19 and Cancer Care. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Various environmental factors can alter the gut microbiome's composition and functionality, and modulate host health. In this study, the effects of oral and parenteral administration of two poorly bioavailable antibiotics (i.e., vancomycin and streptomycin) on male Wistar Crl/Wi(Han) rats for 28 days were compared to distinguish between microbiome-derived or -associated and systemic changes in the plasma metabolome. The resulting changes in the plasma metabolome were compared to the effects of a third reference compound, roxithromycin, which is readily bioavailable. A community analysis revealed that the oral administration of vancomycin and roxithromycin in particular leads to an altered microbial population. Antibiotic-induced changes depending on the administration routes were observed in plasma metabolite levels. Indole-3-acetic acid (IAA) and hippuric acid (HA) were identified as key metabolites of microbiome modulation, with HA being the most sensitive. Even though large variations in the plasma bile acid pool between and within rats were observed, the change in microbiome community was observed to alter the composition of the bile acid pool, especially by an accumulation of taurine-conjugated primary bile acids. In-depth investigation of the relationship between microbiome variability and their functionality, with emphasis on the bile acid pool, will be necessary to better assess the potential adverseness of environmentally induced microbiome changes.

At the 2019 annual meeting of the European Environmental Mutagen and Genomics Society a workshop session related to the use of read across concepts in toxicology was held. The goal of this session was to provide the audience an overview of general read-across concepts. From ECHA's read across assessment framework, the starting point is chemical similarity. There are several approaches and algorithms available for calculating chemical similarity based on molecular descriptors, distance/similarity measures and weighting schemata for specific endpoints. Therefore, algorithms that adapt themselves to the data (endpoint/s) and provide a good ability to distinguish between structural similar and not similar molecules regarding specific endpoints are needed and their use discussed. Toxico-dynamic end points are usually in the focus of read across cases. However, without appropriate attention to kinetics and metabolism such cases are unlikely to be successful. To further enhance the quality of read across cases new approach methods can be very useful. Examples based on a biological approach using plasma metabolomics in rats are given. Finally, with the availability of large data sets of structure activity relationships, in silico tools have been developed which provide hitherto undiscovered information. Automated process is now able to assess the chemical - activity space around the molecule target substance and examples are given demonstrating a high predictivity for certain endpoints of toxicity. Thus, this session provides not only current state of the art criteria for good read across, but also indicates how read-across can be further developed in the near future., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We study the hypergeometric functions associated to five one-parameter deformations of Delsarte K3 quartic hypersurfaces in projective space. We compute all of their Picard-Fuchs differential equations; we count points using Gauss sums and rewrite this in terms of finite-field hypergeometric sums; then we match up each differential equation to a factor of the zeta function, and we write this in terms of global L -functions. This computation gives a complete, explicit description of the motives for these pencils in terms of hypergeometric motives., (© The Author(s) 2020.)

Hexamoll ® DINCH is an important alternative to phthalate plasticizers. Although regulatory reviews have not identified any potential hazards even in sensitive populations, an in vitro study by Campioli et al. (2015) suggested Hexamoll ® DINCH might alter fat storage in adipocytes resulting in obesity. To evaluate this hypothesis, data from studies with Hexamoll ® DINCH were reviewed for evidence of deposition in fat, changes in body weight, or changes in serum chemistry reflecting altered metabolic status. Body weights of F1 and F2 pups in a two-generation study did not differ from controls even at 1000 mg Hexamoll ® DINCH/kg body weight. Mean relative liver weights from the 1000 and 300 mg/kg bw groups were increased, but without histopathologic changes. Triglyceride and cholesterol levels in serum were not affected. In addition, subchronic and chronic studies in rats did not give evidence of an obesogenic effect. Radioactivity from 20 or 1000 mg/kg bw 14 C-labelled Hexamoll ® DINCH dosed orally remained 2-3 times longer in adipose tissue than in well-perfused tissues; however, levels were 20-500% below other tissues at 1 and 8 h post dosing. Radioactivity concentrations in organs and tissues excluding the GI tract declined rapidly and continuously, and decreased in parallel to the concentration in plasma during the following 20 h. Both, initial and terminal half-lives of radioactivity concentration do not indicate a potential for accumulation. Furthermore, a metabolomic comparison of Hexamoll ® DINCH with DEHP and other phthalates shows complete separation of the metabolomic profile of these two chemical classes, meaning that their effects on the body and the body's reaction to the substance are different. Hence, comprehensive in vivo data do not show any evidence of Hexamoll ® DINCH altering fat metabolism or having obesogenic properties., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Liver toxicity is a leading systemic toxicity of drugs and chemicals demanding more human-relevant, high throughput, cost effective in vitro solutions. In addition to contributing to animal welfare, in vitro techniques facilitate exploring and understanding the molecular mechanisms underlying toxicity. New 'omics technologies can provide comprehensive information on the toxicological mode of action of compounds, as well as quantitative information about the multi-parametric metabolic response of cellular systems in normal and patho-physiological conditions. Here, we combined mass-spectroscopy metabolomics with an in vitro liver toxicity model. Metabolite profiles of HepG2 cells treated with 35 test substances resulted in 1114 cell supernatants and 3556 intracellular samples analyzed by metabolomics. Control samples showed relative standard deviations of about 10-15%, while the technical replicates were at 5-10%. Importantly, this procedure revealed concentration-response effects and patterns of metabolome changes that are consistent for different liver toxicity mechanisms (liver enzyme induction/inhibition, liver toxicity and peroxisome proliferation). Our findings provide evidence that identifying organ toxicity can be achieved in a robust, reliable, human-relevant system, representing a non-animal alternative for systemic toxicology.