Basic concepts of mixture toxicity and relevance for risk evaluation and regulation

Exposure to multiple substances is a challenge for risk evaluation. Currently, there is an ongoing debate if generic “mixture assessment/allocation factors” (MAF) should be introduced to increase public health protection. Here, we explore concepts of mixture toxicity and the potential influence of mixture regulation concepts for human health protection. Based on this analysis, we provide recommendations for research and risk assessment. One of the concepts of mixture toxicity is additivity. Substances may act additively by affecting the same molecular mechanism within a common target cell, for example, dioxin-like substances. In a second concept, an “enhancer substance” may act by increasing the target site concentration and aggravating the adverse effect of a “driver substance”. For both concepts, adequate risk management of individual substances can reliably prevent adverse effects to humans. Furthermore, we discuss the hypothesis that the large number of substances to which humans are exposed at very low and individually safe doses may interact to cause adverse effects. This commentary identifies knowledge gaps, such as the lack of a comprehensive overview of substances regulated under different silos, including food, environmentally and occupationally relevant substances, the absence of reliable human exposure data and the missing accessibility of ratios of current human exposure to threshold values, which are considered safe for individual substances. Moreover, a comprehensive overview of the molecular mechanisms and most susceptible target cells is required. We conclude that, currently, there is no scientific evidence supporting the need for a generic MAF. Rather, we recommend taking more specific measures, which focus on compounds with relatively small ratios between human exposure and doses, at which adverse effects can be expected

Ecological Effects of Daily Antiseptic Treatment on Microbial Composition of Saliva-Grown Microcosm Biofilms and Selection of Resistant Phenotypes

Antiseptics are widely used in dental practice and included in numerous over-the-counter oral care products. However, the effects of routine antiseptic use on microbial composition of oral biofilms and on the emergence of resistant phenotypes remain unclear. Microcosm biofilms were inoculated from saliva samples of four donors and cultured in the Amsterdam Active Attachment biofilm model for 3 days. Then, they were treated two times daily with chlorhexidine digluconate (CHX) or cetylpyridinium chloride (CPC) for a period of 7 days. Ecological changes upon these multiple antiseptic treatments were evaluated by semiconductor-based sequencing of bacterial 16S rRNA genes and identification of amplicon sequence variants (ASVs). Furthermore, culture-based approaches were used for colony-forming units (CFU) assay, identification of antiseptic-resistant phenotypes using an agar dilution method, and evaluation of their antibiotic susceptibilities. Both CHX and CPC showed only slight effects on CFU and could not inhibit biofilm growth despite the two times daily treatment for 7 days. Both antiseptics showed significant ecological effects on the microbial compositions of the surviving microbiota, whereby CHX led to enrichment of rather caries-associated saccharolytic taxa and CPC led to enrichment of rather gingivitis-associated proteolytic taxa. Antiseptic-resistant phenotypes were isolated on antiseptic-containing agar plates, which also exhibited phenotypic resistance to various antibiotics. Our results highlight the need for further research into potential detrimental effects of antiseptics on the microbial composition of oral biofilms and on the spread of antimicrobial resistance in the context of their frequent use in oral healthcare

Phenotypic Adaptation to Antiseptics and Effects on Biofilm Formation Capacity and Antibiotic Resistance in Clinical Isolates of Early Colonizers in Dental Plaque

Despite the wide-spread use of antiseptics in dental practice and oral care products, there is little public awareness of potential risks associated with antiseptic resistance and potentially concomitant cross-resistance. Therefore, the aim of this study was to investigate potential phenotypic adaptation in 177 clinical isolates of early colonizers of dental plaque (Streptococcus, Actinomyces, Rothia and Veillonella spp.) upon repeated exposure to subinhibitory concentrations of chlorhexidine digluconate (CHX) or cetylpyridinium chloride (CPC) over 10 passages using a modified microdilution method. Stability of phenotypic adaptation was re-evaluated after culture in antiseptic-free nutrient broth for 24 or 72 h. Strains showing 8-fold minimal inhibitory concentration (MIC)-increase were further examined regarding their biofilm formation capacity, phenotypic antibiotic resistance and presence of antibiotic resistance genes (ARGs). Eight-fold MIC-increases to CHX were detected in four Streptococcus isolates. These strains mostly exhibited significantly increased biofilm formation capacity compared to their respective wild-type strains. Phenotypic antibiotic resistance was detected to tetracycline and erythromycin, consistent with the detected ARGs. In conclusion, this study shows that clinical isolates of early colonizers of dental plaque can phenotypically adapt toward antiseptics such as CHX upon repeated exposure. The underlying mechanisms at genomic and transcriptomic levels need to be investigated in future studie

Reactor rate modulation oscillation analysis with two detectors in Double Chooz

A θ13 oscillation analysis based on the observed antineutrino rates at the Double Chooz far and near detectors for different reactor power conditions is presented. This approach provides a so far unique simultaneous determination of θ13 and the total background rates without relying on any assumptions on the specific background contributions. The analysis comprises 865 days of data collected in both detectors with at least one reactor in operation. The oscillation results are enhanced by the use of 24.06 days (12.74 days) of reactor-off data in the far (near) detector. The analysis considers the ν¯ e interactions up to a visible energy of 8.5 MeV, using the events at higher energies to build a cosmogenic background model considering fast-neutrons interactions and 9Li decays. The background-model-independent determination of the mixing angle yields sin2(2θ13) = 0.094 ± 0.017, being the best-fit total background rates fully consistent with the cosmogenic background model. A second oscillation analysis is also performed constraining the total background rates to the cosmogenic background estimates. While the central value is not significantly modified due to the consistency between the reactor-off data and the background estimates, the addition of the background model reduces the uncertainty on θ13 to 0.015. Along with the oscillation results, the normalization of the anti-neutrino rate is measured with a precision of 0.86%, reducing the 1.43% uncertainty associated to the expectation. [Figure not available: see fulltext.

Search for light sterile neutrinos with the Double Chooz experiment

The Double Chooz experiment is a reactor antineutrino disappearance experiment located in Chooz, France. It was designed to measure the neutrino mixing angle $\theta_{13}$. The experiment is composed of two liquid scintillator detectors of almost identical design that were able to identify electron antineutrinos from the two Chooz B reactor cores by the unique signal of the inverse beta decay. The far detector at an average baseline of 1050 m from the two reactor cores was in operation from April 2011 to the beginning of 2018. The near detector at an average baseline of 400 m has been operating from the beginning of 2015 to the beginning of 2018. A neutrino oscillation analysis can be setup independently from any theoretical model of the reactor neutrino flux utilizing the different baselines of near and far detector relying only on the comparison of near and far detector data. In doing so, all correlated systematics cancel and the analysis is protected against potential bias due to a mismatch of reactor neutrino prediction and data. Apart from its original design goal to measure $\theta_{13}$, Double Chooz is sensitive to so called light sterile neutrinos. Sterile neutrinos are neutrino states that do not take part in the weak interaction but may lead to additional disappearance of the known neutrino states, if they mix with the latter. That mixing is described by additional neutrino squared mass differences and mixing angles. The 3+1 model assumes one additional sterile state. Here, Double Chooz is sensitive to the new mixing angle $\theta_{14}$ depending on the new squared mass difference $\Delta m^2_{41}$ if it is in the range of $0.003\,\mathrm{eV}^2 \lesssim \Delta m^2_{41} \lesssim 0.3\, \mathrm{eV}^2$. This work presents the analysis of Double Chooz data with respect to sterile neutrinos. A Poissonian likelihood fit approach not relying on reactor model predictions is used. It is found that the Double Chooz data is with a p-value of $24.7\% \pm 2.2\%$ consistent with the no-sterile (i.e. $\theta_{14}=0$) hypothesis. The upper limit on $\sin^2 2 \theta_{14}$ at 95% confidence level is given as a function of $\Delta m^2_{41}$

ENDOCARDITE INFECCIOSA: ÍNDICE DE POSITIVIDADE E PERFIL MICROBIOLÓGICO NO HOSPITAL DE CLÍNICAS DE PORTO ALEGRE

Introdução/Objetivo: A endocardite infecciosa é uma inflamação do endocárdio e das válvulas cardíacas comumente causada por microrganismos. Entre os fatores de risco estão o uso de dispositivos cardíacos, doença valvar e diabetes mellitus. A incidência, considerada rara, é de 3 a 10 casos a cada 100.000 pessoas; entretanto, é potencialmente fatal e de difícil diagnóstico. A mortalidade intra-hospitalar é de cerca de 18% e a mortalidade em um ano chega a 40%, atingindo principalmente idosos. Para o diagnóstico laboratorial, a hemocultura é o padrão ouro, porém, em grande parte dos casos, as infecções são causadas por bactérias fastidiosas, resultando em uma hemocultura negativa mesmo na presença do patógeno. O objetivo deste estudo foi avaliar a taxa de positividade e os patógenos identificados em amostras de hemocultura de pacientes com suspeita de endocardite internados no Hospital de Clínicas de Porto Alegre. Métodos: Foi realizado um estudo transversal descritivo retrospectivo utilizando os dados do sistema de informática laboratorial do período 2018 a 2022. Hemoculturas provenientes de pacientes internados com suspeita de endocardite foram incubadas no sistema Bact/Alert (bioMérieux, França) e a identificação bacteriana foi realizada pelo Vitek©MS (bioMérieux, França). Resultados: No período analisado, foram encaminhadas amostras de 691 pacientes para pesquisa de endocardite com uma taxa de positividade de 6,8% (n = 47). As bactérias mais prevalentes foram as espécies de Staphylococcus coagulase negativa 47% (n = 22), dentre elas Staphylococcus epidermidis (n = 8), Staphylococcus hominis (n = 8) foram as mais frequentes, seguido de Staphylococcus capitis (n = 3), Staphylococcus haemolyticus (n = 2) e Staphylococcus lugdunensis (n = 1). Staphylococcus aureus foi detectado em 36% (n = 17) dos pacientes. Os demais patógenos identificados foram: Klebsiella pneumoniae (n = 3), Pseudomonas aeruginosa (n = 2), Serratia marcescens (n = 1), Enterobacter spp. (n = 1) e Acinetobacter lwoffii (n = 1). Um total de 70% dos pacientes (n = 33) tiveram duas amostras de hemocultura positivas para o mesmo microrganismo. Conclusão: Este estudo indicou um predomínio de Staphylococcus em pacientes com suspeita de endocardite infecciosa. No entanto, não é possível definir a doença apenas com os dados microbiológicos pois, conforme Duke-ISCVID IE Criteria (2023), a avaliação dos dados clínicos e exames de imagem são necessários para complementar o diagnóstico

AUMENTO DE CASOS DE INFLUENZA B EM PACIENTES DE UM HOSPITAL TERCIÁRIO DO SUL DO BRASIL EM 2023

Introdução: Os vírus Influenza A e B (FLU A e B) são responsáveis por epidemias sazonais, sendo considerados os agentes etiológicos mais comumente relacionados às síndromes respiratórias agudas. Segundo a atualização mais recente do Sistema Global de Vigilância e Resposta à Influenza, 63,7% dos casos globais de influenza foram devido a um dos subtipos de FLU A e 36,3% são casos de FLU B. Este estudo procurou relatar os casos de FLU A e B no contexto de um hospital terciário do Sul do país. Métodos: Foi realizado um estudo transversal descritivo no período de fevereiro de 2022 a maio de 2023 para identificar a positividade dos vírus FLU A e B. Foram avaliados os resultados dos exames encaminhados para o Laboratório de Biologia Molecular do Hospital de Clínicas de Porto Alegre para pesquisa de vírus respiratório (Resp-4-Plex, Abbott Molecular Inc., EUA). Resultados: Foram realizados 7.556 exames para a pesquisa de vírus respiratórios na instituição no período de fevereiro de 2022 a maio de 2023. Desse total, 5,1% (386/7.556) apresentaram positividade para FLU A e 1,37% (104/7.556) apresentaram positividade para FLU B. No ano de 2022, o período de maior positividade foi entre fevereiro e maio, em que foram realizados 1.569 testes, com uma taxa de 5,22% (82/1.569) de positivos para FLU A e 0,38% (6/1.569) positivos para FLU B. No mesmo período no ano de 2023 foram realizados 1.616 testes, sendo 9,28% (150/1.616) casos positivos para FLU A e 5,07% (82/1.616) casos positivos para FLU B. Essa taxa de positividade entre os períodos analisados reflete um aumento na circulação do FLU B quando comparado a 2022 que correspondia a 6,8% do total de casos de influenza e em 2023 está representando 35,3% dos casos. Conclusões: Nos últimos anos os vírus respiratórios apresentaram uma alteração no perfil de transmissão, principalmente devido à pandemia de COVID-19. Essa mudança de comportamento deve-se tanto à predominância do SARS-CoV-2 quanto à adoção de medidas de prevenção como uso de máscaras e isolamento social. Entretanto, a falta crônica da exposição natural ao vírus, sustentada a outros subtipos do vírus influenza pode ter impactado no aumento da circulação do FLU B após esse período de medidas de restrição. Essa mudança de comportamento ressalta a importância da vigilância genômica e do conhecimento do perfil epidemiológico desses vírus e esses dados reforçam a importância de uma cobertura vacinal adequada para reduzir os impactos no sistema público de saúde