Tenofovir induced acute kidney injury in a patient with unilateral renal agenesis despite initially non-impaired renal function

Nephrotoxicity is observed in 1.6 % of patients treated with tenofovir disoproxil fumarat Fux 2007

Immunogenity of the pneumococcal polysaccharide vaccine in COPD patients. The effect of systemic steroids

AbstractRationale: To investigate if systemic steroids influence the antibody response to the 23-valent pneumococcal polysaccaride vaccine (23-PPV) in COPD patients.Patients and methods: COPD patients on: (a)⩾10mg of prednisolone/day (SS, n=30); (b) inhalative steroids (IS, n=30); (c) controls without COPD (CG, n=29) were vaccinated with 23-PPV. The concentration (μg/ml) of capsular specific anti-pneumococcal IgG antibodies (AB) for the serotypes (PNC) 4,6B,9V,14,18C,19F,23F were measured by Elisa technique before, 3 and 12 months (m) after vaccination. Non-responders were defined when AB-concentrations did neither doubled nor reach ⩾1μg/ml.Results: N=24 (CG), n=29 (IS), n=18 (SS) patients completed the study (mean age 64yrs.). Serious adverse events were not observed. Geometric mean (GM) AB-concentration of all serotypes increased significantly (CG, IS, SS) 3 and 12m after vaccination (P<0.05). The percentage of non-responders ranged between 16% (PNC 19F, IS) and 65% (PNC 4, SS) after 3m and 21% (PNC 19F, IS) and 82% (PNC 4, CG) after 12m. Neither post-vaccine AB-concentrations (3 and 12m) nor the rate of non-responders differed significantly between patients on systemic steroids and the other groups (IS, CG).Conclusions: Systemic steroids did not influence the AB-response. In all groups mean AB-concentration increased significantly after vaccination but an important percentage of subjects of all three groups were non-responders

Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment

Human biomonitoring (HBM) data can provide insight into co-exposure patterns resulting from exposure to multiple chemicals from various sources and over time. Therefore, such data are particularly valuable for assessing potential risks from combined exposure to multiple chemicals. One way to interpret HBM data is establishing safe levels in blood or urine, called Biomonitoring Equivalents (BE) or HBM health based guidance values (HBM-HBGV). These can be derived by converting established external reference values, such as tolerable daily intake (TDI) values. HBM-HBGV or BE values are so far agreed only for a very limited number of chemicals. These values can be established using physiologically based kinetic (PBK) modelling, usually requiring substance specific models and the collection of many input parameters which are often not available or difficult to find in the literature. The aim of this study was to investigate the suitability and limitations of generic PBK models in deriving BE values for several compounds with a view to facilitating the use of HBM data in the assessment of chemical mixtures at a screening level. The focus was on testing the methodology with two generic models, the IndusChemFate tool and High-Throughput Toxicokinetics package, for two different classes of compounds, phenols and phthalates. HBM data on Danish children and on Norwegian mothers and children were used to evaluate the quality of the predictions and to illustrate, by means of a case study, the overall approach of applying PBK models to chemical classes with HBM data in the context of chemical mixture risk assessment. Application of PBK models provides a better understanding and interpretation of HBM data. However, the study shows that establishing safety threshold levels in urine is a difficult and complex task. The approach might be more straightforward for more persistent chemicals that are analysed as parent compounds in blood but high uncertainties have to be considered around simulated metabolite concentrations in urine. Refining the models may reduce these uncertainties and improve predictions. Based on the experience gained with this study, the performance of the models for other chemicals could be investigated, to improve the accuracy of the simulations

Clinically Approved Drugs Inhibit the Staphylococcus aureus Multidrug NorA Efflux Pump and Reduce Biofilm Formation

Staphylococcus aureus has acquired resistance to antibiotics since their first use. The S. aureus protein NorA, an efflux pump belonging to the major facilitator superfamily (MFS), contributes to resistance to fluoroquinolones (e.g., ciprofloxacin), biocides, dyes, quaternary ammonium compounds, and antiseptics. Different compounds have been identified as potential efflux pump inhibitors (EPIs) of NorA that result in increased intracellular concentration of antibiotics, restoring their antibacterial activity and cell susceptibility. However, none of the currently known EPIs have been approved for clinical use, probably due to their toxicity profiles. In the present study, we screened approved drugs for possible efflux pump inhibition. By screening a compound library of approximately 1200 different drugs, we identified nilotinib, a tyrosine kinase inhibitor, as showing the best efflux pump inhibitory activity, with a fractional inhibitory concentration index of 0.1875, indicating synergism with ciprofloxacin, and a minimum effective concentration as low as 0.195 μM. Moreover, at 0.39 μM, nilotinib, in combination with 8 μg/mL of ciprofloxacin, led to a significant reduction in biofilm formation and preformed mature biofilms. This is the first description of an approved drug that can be used as an efflux pump inhibitor and to reduce biofilms formation at clinically achievable concentrations

Molecular epidemiology of SARS-CoV-2: a regional to global perspective

Background After a year of the global SARS-CoV-2 pandemic, a highly dynamic genetic diversity is surfacing. Among nearly 1000 reported virus lineages, dominant lineages such as B.1.1.7 or B.1.351 attract media attention with questions regarding vaccine efficiency and transmission potential. In response to the pandemic, the Jena University Hospital began sequencing SARS-CoV-2 samples in Thuringia in early 2020.Methods Viral RNA was sequenced in tiled amplicons using Nanopore sequencing. Subsequently, bioinformatic workflows were used to process the generated data. As a genomic background, 9,642 representative SARS-CoV-2 genomes (1,917 of German origin) were extracted from more than 300.000 genomes.Results In a comprehensive bioinformatics analysis, we have set Thuringian isolates in the German, European and global context. In Thuringia, a largely rural German region without an international airport and a population density below the German average, we discovered many of the common “EU lineages”. German samples are scattered across eight major clades, and Thuringian samples occupy four of them.Conclusion The rapid emergence and spread of novel variants are of great concern as these lineages could transmit more efficiently, evade current vaccine efforts or undermine diagnostic test accuracy. To anticipate and mitigate these threats, a continuous molecular surveillance is essential.Key messagesBioinformatics analysis of 1,917, 4,251, and 3,474 SARS-CoV-2 genomes from Germany, the EU (except Germany), and non-EU, respectively, subsampled from more than 300,000 public genomes and placed in the context of Thuringian sequencesConstant antigenic drift for SARS-CoV-2 and no clear pattern or clustering is visible in Thuringia based on the current number of samplesCurrently over 100 described lineages are identified in Germany and only a subset (9) are detected in Thuringia so far, most likely due to genetic undersamplingFrom a national perspective, it is likely that high-frequency lineages, which are currently spreading throughout Europe, will eventually also reach ThuringiaSystematic and dense molecular surveillance via whole-genome sequencing is needed to detect concerning new lineages early, limit spread and adjust vaccines if necessaryCompeting Interest StatementThe authors have declared no competing interest.Funding StatementThe work is funded by the German Ministry of Education and Research (BMBF), grant number 01KX2021, and the Thuringian Region Government, grant number TZUZI82094.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:not applicableAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data is available on GISAID.Introduction Methods - Nanopore sequencing and genome reconstruction - Time tree creation Results - Most highly prevalent SARS-CoV-2 lineages in Germany detected in Thuringia - Genetic divergence and current lineage distribution Discussio

Automated and rapid identification of multidrug resistant Escherichia coli against the lead drugs of acylureidopenicillins, cephalosporins, and fluoroquinolones using specific Raman marker bands

A Raman-based, strain-independent, semi-automated method is presented that allows the rapid (<3 hours) determination of antibiotic susceptibility of bacterial pathogens isolated from clinical samples. Applying a priori knowledge about the mode of action of the respective antibiotic, we identified characteristic Raman marker bands in the spectrum and calculated batch-wise weighted sum scores from standardized Raman intensity differences between spectra of antibiotic exposed and nonexposed samples of the same strains. The lead substances for three relevant antibiotic classes (fluoroquinolone ciprofloxacin, third-generation cephalosporin cefotaxime, ureidopenicillin piperacillin) against multidrug-resistant Gram-negative bacteria (MRGN) revealed a high sensitivity and specificity for the susceptibility testing of two Escherichia coli laboratory strains and 12 clinical isolates. The method benefits from the parallel incubation of control and treated samples, which reduces the variance due to alterations in cultivation conditions and the standardization of differences between batches leading to long-term comparability of Raman measurements. © 2020 The Authors. Journal of Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei

Towards a qAOP Framework for Predictive Toxicology - Linking Data to Decisions

The adverse outcome pathway (AOP) is a conceptual construct that facilitates organisation and interpretation of mechanistic data representing multiple biological levels and deriving from a range of methodological approaches including in silico, in vitro and in vivo assays. AOPs are playing an increasingly important role in the chemical safety assessment paradigm and quantification of AOPs is an important step towards a more reliable prediction of chemically induced adverse effects. Modelling methodologies require the identification, extraction and use of reliable data and information to support the inclusion of quantitative considerations in AOP development. An extensive and growing range of digital resources are available to support the modelling of quantitative AOPs, providing a wide range of information, but also requiring guidance for their practical application. A framework for qAOP development is proposed based on feedback from a group of experts and three qAOP case studies. The proposed framework provides a harmonised approach for both regulators and scientists working in this area

International Perspective on the New 2019 American Thoracic Society/Infectious Diseases Society of America Community-Acquired Pneumonia Guideline:A Critical Appraisal by a Global Expert Panel

In 2019, the American Thoracic Society (ATS) / Infectious Diseases Society of America (IDSA) issued a substantial revision of the 2007 guideline on community-acquired pneumonia (CAP). Despite generalization of infectious disease guidelines is limited due substantial geographic differences in microbiological etiology and antimicrobial resistance, the ATS/IDSA guidelines are frequently applied outside the USA. Therefore, this project aimed to give a perspective on the ATS/IDSA CAP recommendations related to the management of CAP outside of the USA. For this, an expert panel comprised of 14 international key opinion leaders in the field of CAP from 10 countries across 5 continents, who were not involved in the 2019 guideline, was asked to subjectively name the five most useful, the most critical and the recommendation that can not be applied to their respective region. There was no formal consensus process and the paper reflects different opinions. Recommendations welcomed by the vast majority of the international pneumonia experts included the abandonment of the concept of "health-care associated pneumonia" (HCAP), the more restrictive indication for empiric macrolide treatment in outpatients, the increased emphasis on microbiological diagnostics, and addressing the use of corticosteroids. Main criticisms included the somewhat arbitrary choice of a 25% resistance threshold for outpatient macrolide monotherapy. Experts from areas with elevated mycobacterial prevalence particularly opposed the recommendation of fluoroquinolones, even as an alternative

SARS Clinical Features, United States, 2003

We compared the clinical features of 8 U.S. case-patients with laboratory-confirmed severe acute respiratory syndrome (SARS) to 65 controls who tested negative for SARS coronavirus (SARS-CoV) infection. Shortness of breath, vomiting, diarrhea, progressive bilateral infiltrates on chest radiograph, and need for supplemental oxygen were significantly associated with confirmed SARS-CoV infection