Two other studies assessed the transcriptomic profile during

Two other studies assessed the transcriptomic profile during the early hours of sepsis in whole blood (Lissauer et al., 2009; Johnson et al., 2007). Results of both studies revealed increased Aminoallyl-dCTP - Cy3 of TLR5 as well as mediators of apoptosis similar to the present study. Overall, the increasing number of proof-of-concept studies suggests that transcriptomic profiling is technically feasible and leads to reproducible findings indicative of sub-categories of the host response that are not accessible to clinical diagnosis or conventional single-protein biomarkers. Furthermore, a most recent study confirms the potential of limited numbers of transcripts as biomarkers to classify patients with systemic inflammation on the ICU (McHugh et al., 2015). The present findings based on a three-step approach and comprising confirmation in two independent cohorts introduce a new genomic biomarker that can separate critically ill patients with infection from those without infection. The biomarker behaves similarly among patients with clinical signs of infection with or without confirmatory microbiology; these are used as a positive infection group to simulate the everyday clinical scenario where microbiology findings either fail or delay considerably. One of its basic components, namely the DOWN-score, changes very early i.e. within the first 24h indicating prognosis, allowing to identify a population-at-risk with a good sensitivity but limited specificity that might be included in studies aiming to improve mortality. Such strategies are increasingly recognized as an option to avoid doing harm in patients ultimately surviving without immunomodulatory interventions when aiming to attenuate a principally adaptive response to infection (Singer and Glynne, 2005).
Conclusions
Funding The works were supported by the BMBF within the framework of the “MetaZIK”/ZIK Septomics Jena (03Z2J521), the Thuringian Ministry of Education, Science and Art (projects B-309-00014 and A 309-04002), and by Thüringer Aufbaubank (“RNA Score 2007 FE 014”). Part of the study was funded by the Hellenic Institute for the Study of Sepsis.
Competing Interest
Ethics Statement
Author Contributions
Abbreviations
Acknowledgment
Introduction Recent estimates are that one million children developed tuberculosis (TB) in 2010 alone (Jenkins et al., 2014). In babies and toddlers, TB manifests as disseminated disease, attributed to poor immune containment (Newton et al., 2008). In disseminated disease, Mycobacterium tuberculosis (Mtb) is predominantly intracellular as opposed to the predominantly extracellular bacteria in cavitary pneumonia in adults. However, therapeutic regimens used to treat pediatric TB were copied from those for adults with pulmonary TB. For multi-drug resistant TB (MDR-TB) and extensively drug-resistant TB in children, no regimens have been developed as of yet and in some parts of the world such children are left untreated, and have been deemed “invisible” (Becerra and Swaminathan, 2014; Dheda et al., 2014). There has been reluctance to perform dose–response studies and first in human studies in children because of concerns for toxicity such as drug induced liver injury (DILI). Indeed, the incidence of DILI among children treated for TB ranges between 1.7–8%, making this a legitimate concern (Devrim et al., 2010; Roy et al., 2006) Recently, the World Health Organization and STOP-TB have advocated for the design of new and shorter treatment regimens for children, leading to zero TB deaths in children. Thus the problem is pressing. Recently Momper et al. (2015) summarized reasons for failed clinical trials in all pediatric drug development as mainly due to lack of efficacy, poor dosing, or toxicity; they proposed use of pre-clinical models to tackle these failures so that results could be directly translated to the clinic. No pre-clinical model of intracellular TB has been designed as of yet. On the other hand, preclinical toxicity requires multiple animal model species testing. Regardless, rodent models which are commonly used as one of the animals\'models have predictive rates of less than 40% for human DILI and resulted in second highest discontinuation rates for several drugs (Olson et al., 2000). In “Preventing drug-induced liver injury: how useful are animal models?” Ballet argues that no animal models are useful for predicting the most common forms of human DILI at all and that humans themselves are best models for DILI (Ballet, 2015). Indeed, no good pre-clinical model of DILI in which human concentration-time profiles of pharmaceuticals are examined exists as of yet. Here, we designed a model of intracellular TB, fitted a 3-dimensional human organoid liver (3D-liver), and dialed human pediatric-like pharmacokinetics, for performance of pediatric dose–response studies to estimate both safety and DILI at the same time.