Human parechovirus 3 in infants: expanding our knowledge of adverse outcomes

Human parechovirus particularly genotype 3 (HPeV3) is an emerging infection affecting predominantly young infants. The potential for neurologic sequelae in a vulnerable subset is increasingly apparent. A review of 2 epidemics of human parechovirus (HpeV) infection in 2013 and in 2015 in Queensland, Australia, was undertaken, with an emphasis on identifying adverse neurodevelopmental outcome.All hospitalized cases with laboratory-confirmed HPeV infection between October 2013 June 2016 were identified. Clinical, demographic, laboratory and imaging data were collected and correlated with reported developmental outcome.Laboratory-confirmed HPeV infections were identified in 202 patients across 25 hospitals; 86.6% (n = 175) were younger than 3 months 16.3% (n = 33) received intensive care admission. Of 142 cerebrospinal fluid samples which were HPeV polymerase chain reaction positive, all 89 isolates successfully genotyped were HPeV3. Clinical information was available for 145 children; 53.1% (n = 77) had follow-up from a pediatrician, of whom 14% (n = 11) had neurodevelopmental sequelae, ranging from hypotonia and gross motor delay to spastic quadriplegic cerebral palsy and cortical visual impairment. Of 15 children with initially abnormal brain magnetic resonance imaging, 47% (n = 7) had neurodevelopmental concerns, the remainder had normal development at follow-up between 6 and 15 months of age.This is the largest cohort of HPeV3 cases with clinical data and pediatrician-assessed neurodevelopmental follow-up to date. Developmental concerns were identified in 11 children at early follow-up. Abnormal magnetic resonance imaging during acute infection did not specifically predict poor neurodevelopmental in short-term follow-up. Continued follow-up of infants and further imaging correlation is needed to explore predictors of long-term morbidity

Residue-Ligand Interaction Energy (ReLIE) on a Receptor-Dependent 3D-QSAR Analysis of S- and NH-DABOs as Non-Nucleoside Reverse Transcriptase Inhibitors

<em></em>A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by receptor-dependent (RD) three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to derive RD-3D-QSAR models. The descriptors in this new method are the steric and electrostatic interaction energies of the protein-ligand complexes (per residue) simulated by molecular dynamics, an approach named <em>Residue-Ligand Interaction Energy </em>(ReLIE). This study was performed using a training set of 59 compounds and the MKC-442/RT complex structure as reference. The ReLIE-3D-QSAR models were constructed and evaluated by genetic algorithm (GA) and partial least squares (PLS). In the best equations, at least one term is related to one of the amino acid residues of the p51 subunit: <em>Asn136, Asn137, Glu138</em>, and <em>Thr139</em>. This fact implies the importance of interchain interaction (p66-p51) in the equations that best describe the structure-activity relationship for this class of compounds. The best equation shows q<sup>2</sup> = 0.660, SE<sub>cv</sub> = 0.500, r<sup>2</sup> = 0.930, and SEE = 0.226. The external predictive ability of this best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, substituents capable of interactions with residues like I<em>le94, Lys101, Tyr181</em>, and <em>Tyr188 </em>should be selected. Also, given the importance of the conserved Asn136, this residue could become an attractive target for the design of novel NNRTIs with improved potency and increased ability to avoid the development of drug-resistant viruses