Dataset Information

The Added Value of Longitudinal Imaging for Preclinical In Vivo Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis.

ABSTRACT: Brain infections with Cryptococcus neoformans are associated with significant morbidity and mortality. Cryptococcosis typically presents as meningoencephalitis or fungal mass lesions called cryptococcomas. Despite frequent in vitro discoveries of promising novel antifungals, the clinical need for drugs that can more efficiently treat these brain infections remains. A crucial step in drug development is the evaluation of in vivo drug efficacy in animal models. This mainly relies on survival studies or postmortem analyses in large groups of animals, but these techniques only provide information on specific organs of interest at predefined time points. In this proof-of-concept study, we validated the use of noninvasive preclinical imaging to obtain longitudinal information on the therapeutic efficacy of amphotericin B or fluconazole monotherapy in meningoencephalitis and cryptococcoma mouse models. Bioluminescence imaging enabled the rapid in vitro and in vivo evaluation of drug efficacy, while complementary high-resolution anatomical information obtained by magnetic resonance imaging of the brain allowed a precise assessment of the extent of infection and lesion growth rates. We demonstrated a good correlation between both imaging readouts and the fungal burden in various organs. Moreover, we identified potential pitfalls associated with the interpretation of therapeutic efficacy based solely on postmortem studies, demonstrating the added value of this noninvasive dual imaging approach compared to standard mortality curves or fungal load endpoints. This novel preclinical imaging platform provides insights in the dynamic aspects of the therapeutic response and facilitates a more efficient and accurate translation of promising antifungal compounds from bench to bedside.

SUBMITTER: Vanherp L

PROVIDER: S-EPMC7318040 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The Added Value of Longitudinal Imaging for Preclinical In Vivo Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis.

Vanherp Liesbeth L Poelmans Jennifer J Hillen Amy A Janbon Guilhem G Brock Matthias M Lagrou Katrien K Vande Velde Greetje G Himmelreich Uwe U

Antimicrobial agents and chemotherapy 20200623 7

Brain infections with Cryptococcus neoformans are associated with significant morbidity and mortality. Cryptococcosis typically presents as meningoencephalitis or fungal mass lesions called cryptococcomas. Despite frequent in vitro discoveries of promising novel antifungals, the clinical need for drugs that can more efficiently treat these brain infections remains. A crucial step in drug development is the evaluation of in vivo drug efficacy in animal models. This mainly rel ...[more]

PMID: 32284382

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Project description:BackgroundIn present-day life-insurance medical underwriting practice the risk assessment starts with a standard health declaration (SHD). Indication for additional medical screening depends predominantly on age and amount of insured capital. From a medical perspective it is questionable whether there is an association between the level of insured capital and medical risk in terms of mortality. The aim of the study is to examine the prognostic value of parameters from the health declaration and application form on extra mortality based on results from additional medical testing.MethodsA history register-based cohort study was conducted including about 15.000 application files accepted between 2007 and 2010. Blood pressure, lipids, cotinine and glucose levels were used as dependent variables in logistic regression models. Resampling validation was applied using 250 bootstrap samples to calculate area under the curves (AUC's). The AUC was used to discriminate between persons with and without at least 25% extra mortality.ResultsBMI and the overall assessment of the health declaration by an insurance physician or medical underwriter showed the strongest discrimination in multivariable analysis. Including all variables at minimum cut-off levels resulted in an AUC of 0.710 while by using a model with BMI, the assessment of the health declaration and gender, the AUC was 0.708. Including all variables at maximum cut-off levels lead to an AUC of 0.743 while a model with BMI, the assessment of the health declaration and age resulted in an AUC of 0.741.ConclusionsThe outcome of this study shows that BMI and the overall assessment of the health declaration were the dominant variables to discriminate between applicants for life-insurance with and without at least 25 percent extra mortality. The variable insured capital set by insurers as factor for additional medical testing could not be established in this study population. The indication for additional medical testing at underwriting life-insurance can possibly be done on limited variables instead of the obligatory medical testing based on age and the amount of insured capital.

Dataset Information

The Added Value of Longitudinal Imaging for Preclinical In Vivo Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis.

Publications

The Added Value of Longitudinal Imaging for Preclinical <i>In Vivo</i> Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis.

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