ABSTRACT
BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, and herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. In this systematic review, we analyzed the compounds used in hepatotoxicity assays and established a list of DILI-positive and -negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from the COST Action ProEuroDILI Network (CA17112). METHODS: Following 2020 PRISMA guidelines, original research articles focusing on DILI which used in vitro human models and performed at least one hepatotoxicity assay with positive and negative control compounds, were included. Bias of the studies was assessed by a modified 'Toxicological Data Reliability Assessment Tool'. RESULTS: A total of 51 studies (out of 2,936) met the inclusion criteria, with 30 categorized as reliable without restrictions. Although there was a broad consensus on positive compounds, the selection of negative compounds lacked clarity. 2D monoculture, short exposure times and cytotoxicity endpoints were the most tested, although there was no consensus on drug concentrations. CONCLUSIONS: Extensive analysis highlighted the lack of agreement on control compounds for in vitro DILI assessment. Following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative control drugs for validation of in vitro models of DILI is proposed. IMPACT AND IMPLICATIONS: Prediction of human toxicity early in the drug development process remains a major challenge, necessitating the development of more physiologically relevant liver models and careful selection of drug-induced liver injury (DILI)-positive and -negative control drugs to better predict the risk of DILI associated with new drug candidates. Thus, this systematic study has crucial implications for standardizing the validation of new in vitro models of DILI. By establishing a consensus-driven list of positive and negative control drugs, the study provides a scientifically justified framework for enhancing the consistency of preclinical testing, thereby addressing a significant challenge in early hepatotoxicity identification. Practically, these findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory guidelines, ensuring a more systematic and efficient approach to drug safety assessment.
ABSTRACT
It is not possible to systematically screen the environment for rabies virus (RABV) using current approaches. We sought to determine under what conditions RABV is detectable from feces and other accessible samples from infected wildlife to broaden the number of biological samples that could be used to test for RABV. We employed a recently-developed quantitative RT-PCR assay called the "LN34 panlyssavirus real-time RT-PCR assay", which is highly sensitive and specific for all variants of RABV. We harvested and tested brain tissue, fecal, and/or mouth swab samples from 25 confirmed RABV positive bats of six species. To determine if rabies RNA lasts in feces sufficiently long post-defecation to use it as a surveillance tool, we tested fecal samples from 10 bats at the time of sample collection and after 24 hours of exposure to ambient conditions, with an additional test on six bats out to 72 hours. To assess whether we could pool fecal pellets and still detect a positive, we generated dilutions of known positives at 1:1, 1:10, 1:50, and 1:200. For six individuals for which matched brain, mouth swab, and fecal samples were tested, results were positive for 100%, 67%, and 67%, respectively. For the first time test to 24 hours, 63% of feces that were positive at time 0 were still positive after 24 hours, and 50% of samples at 72 hours were positive across all three replicates. Pooling tests revealed that fecal positives were detected at 1:10 dilution, but not at 1:50 or 1:200. Our preliminary results suggest that fecal samples hold promise for a rapid and non-invasive environmental screening system.
Subject(s)
Body Fluids , Chiroptera , Lepidoptera , Rabies virus , Rabies , Humans , Animals , FecesABSTRACT
BACKGROUND: Different modalities of quarantines were one of the main measures implemented worldwide to avoid the spread of SARS-CoV2 virus. AIM: To analyze and compare retrospectively the implementation of the Step- to-Step plan devised by the Chilean Ministry of Health during the pandemic. To propose a decision-making path based on an artificial intelligence fuzzy system to determine confinements in specific territories. MATERIAL AND METHODS: The Step-to-Step Plan threshold values such hospital network capacity, epidemic spreading, testing and contact tracing capability were modeled using fuzzy numbers and fuzzy rule-based systems. RESULTS: Ministry of Health's decision-making opportuneness were unrelated with the Step-to-Step Plan indicators for deconfinement. Such disagreements undermined epidemiological indicators. CONCLUSIONS: Using an artificial intelligence system could improve decision-making transparency, emergency governance, and risk communication to the population.
Subject(s)
Humans , Artificial Intelligence , Quarantine , RNA, Viral , Retrospective Studies , Fuzzy LogicABSTRACT
BACKGROUND: Different modalities of quarantines were one of the main measures implemented worldwide to avoid the spread of SARS-CoV2 virus. AIM: To analyze and compare retrospectively the implementation of the Step- to-Step plan devised by the Chilean Ministry of Health during the pandemic. To propose a decision-making path based on an artificial intelligence fuzzy system to determine confinements in specific territories. MATERIAL AND METHODS: The Step-to-Step Plan threshold values such hospital network capacity, epidemic spreading, testing and contact tracing capability were modeled using fuzzy numbers and fuzzy rule-based systems. RESULTS: Ministry of Health's decision-making opportuneness were unrelated with the Step-to-Step Plan indicators for deconfinement. Such disagreements undermined epidemiological indicators. CONCLUSIONS: Using an artificial intelligence system could improve decision-making transparency, emergency governance, and risk communication to the population.
Subject(s)
Artificial Intelligence , Quarantine , Humans , RNA, Viral , Retrospective Studies , Fuzzy LogicABSTRACT
Mortality of Plutella xylostella (Lepidoptera, Plutellidae) by parasitoids in the Province of Santa Fe, Argentina. Plutella xylostella (Linnaeus, 1758) (Lepidoptera, Plutellidae) larvae cause severe economic damage on cabbage, Brassica oleracea L. variety capitata (Brassicaceae), in the horticultural fields in the Province of Santa Fe, Argentina. Overuse of broad spectrum insecticides affects the action of natural enemies of this insect on cabbage. The objectives of this work were to identify the parasitoids of P. xylostella and to determine their influence on larva and pupa mortality. Weekly collections of larvae and pupae were randomly conducted in cabbage crops during spring 2006 and 2007. The immature forms collected were classified according to their developmental stage: L1 and L2 (Ls = small larvae), L3 (Lm = medium larvae), L4 (Ll = large larvae), pre-pupae and pupae (P). Each individual was observed daily in the laboratory until the adult pest or parasitoid emergence. We identified parasitoids, the number of instar and the percentage of mortality of P. xylostella for each species of parasitoid. Parasitoids recorded were: Diadegma insulare (Cresson, 1875) (Hymenoptera, Ichneumonidae), Oomyzus sokolowskii (Kurdjumov, 1912) (Hymenoptera, Eulophidae), Cotesia plutellae (Kurdjumov, 1912) (Hymenoptera, Braconidae) and an unidentified species of Chalcididae (Hymenoptera). Besides parasitoids, an unidentified entomopathogenic fungus was also recorded in 2006 and 2007. In 2006, the most successful parasitoids were D. insulare and O. sokolowskii, while in 2007 only D. insulare exerted a satisfactory control and it attacked the early instars of the pest.
Mortalidade de Plutella xylostella (Lepidoptera, Plutellidae) por parasitóides na Província de Santa Fé, Argentina. Plutella xylostella (Linnaeus, 1758) (Lepidoptera, Plutellidae) causa danos econômicos severos em repolho, Brassica oleracea variedade capitata L. (Brassicaceae), na área de horticultura localizada na Província de Santa Fé, Argentina. O uso excessivo de inseticidas de largo espectro afeta a ação dos inimigos naturais de P. xylostella em repolho. O presente trabalho teve como objetivo identificar os parasitóides de P. xylostella e determinar sua influência na mortalidade de larvas e pupas em Santa Fé, Argentina. Coletas semanais de larvas e pupas em culturas de repolho foram realizadas aleatoriamente na área durante a primavera de 2006 e 2007, registradas pelo estágio de desenvolvimento: L1 e L2 (Ls = larvas pequenas), (Lm = larvas médias) L3, L4 (Ll = larvas grandes) pré-pupa e pupa (P). Cada indivíduo foi observado diariamente no laboratório até a emergência dos adultos da praga ou dos parasitóides. Foram identificadas as espécies de parasitóides o número de instars e a porcentagem de mortalidade. Os parasitóides registrados foram: Diadegma insulare (Cresson, 1875) (Hymenoptera, Ichneumonidae), Oomyzus sokolowskii (Kurdjumov, 1912) (Hymenoptera, Eulophidae), Cotesia plutellae (Kurdjumov, 1912) (Hymenoptera, Braconidae) e uma espécie não identificada pertencente à família Chalcididae. Além dos parasitóides, um fungo entomopatogênico não identificado foi registrado. Em 2006, os parasitóides mais bem sucedidos foram D. insulare e O. Sokolowskii; enquanto que em 2007 apenas D. insulare exerceu um controle satisfatório, atacando os instares iniciais da praga.