In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ~6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds, and we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, Emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and 3-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, an FDA approved category B anthelmintic drug, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

Recent studies suggest that Attention Deficit Hyperactivity Disorder (ADHD) is a common comorbid condition in childhood epilepsy, but little is known regarding the nature, frequency and timing of associated neurobehavioural/cognitive complications or the underlying aetiology of ADHD in epilepsy. This investigation examined: (i) the prevalence of ADHD and its subtypes; (ii) the association of ADHD with abnormalities in academic, neuropsychological, behavioural and psychiatric status and (iii) the aetiology of ADHD in paediatric epilepsy. Seventy-five children (age 8-18) with new/recent onset idiopathic epilepsy and 62 healthy controls underwent structured interview (K-SADS) to identify the presence and type of DSM-IV defined ADHD, neuropsychological assessment, quantitative MR volumetrics, characterization of parent observed executive function, review of academic/educational progress and assessment of risk factors during gestation and delivery. The results indicate that ADHD is significantly more prevalent in new onset epilepsy than healthy controls (31% versus 6%), characterized predominantly by the inattentive variant, with onset antedating the diagnosis of epilepsy in the majority of children. ADHD in childhood epilepsy is associated with significantly increased rates of school based remedial services for academic underachievement, neuropsychological consequences with prominent differences in executive function, and parent-reported dysexecutive behaviours. ADHD in paediatric epilepsy is neither associated with demographic or clinical epilepsy characteristics nor potential risk factors during gestation and birth. Quantitative MRI demonstrates that ADHD in epilepsy is associated with significantly increased gray matter in distributed regions of the frontal lobe and significantly smaller brainstem volume. Overall, ADHD is a prevalent comorbidity of new onset idiopathic epilepsy associated with a diversity of salient educational, cognitive, behavioural and social complications that antedate epilepsy onset in a significant proportion of cases, and appear related to neurodevelopmental abnormalities in brain structure.

The purpose of this study was to determine the incidence of clinically significant depression occurring between 1 and 4 months postpartum and to investigate whether somatic complaints, subsyndromal depressive symptoms, or birth-related concerns among non-depressed women at 1 month were predictive of postpartum depression. This is a prospective cohort study of 465 women from the Wisconsin Maternity Leave and Health Project (WMLHP). Women who were not depressed at 1 month postpartum were reassessed 3 months later for depression occurring at any time in the interval between 1 and 4 months postpartum. Depression was defined as either meeting the criteria for major depression on the National Institute of Mental Health (NIMH) Diagnostic interview Schedule (DIS) or scoring above 15 on the Center for Epidemiologic Studies Depression Scale (CES-D). Physical symptoms were assessed by an adapted Health Responses Scale. Other measures were developed specifically for the WMLHP. Of 465 women, 27 (5.8%) became clinically depressed between 1 and 4 months postpartum. In a logistic regression analysis, four variables (maternal age, depression during pregnancy, thoughts of death and dying at 1 month postpartum, and difficulty falling asleep at 1 month postpartum) were predictive of depression at 4 months postpartum. Breast-feeding, mode of delivery, family income, parity and mother's education did not predict depression. The existence of subsyndromal depressive symptoms, particularly thoughts of death and dying, may represent a prodromal phase of depression and should alert clinicians to the possibility of future postpartum depression. Women with a history of depression during pregnancy should be monitored for signs of postpartum depression for a minimum of 4 months. Obstetricians are in a unique position during the postpartum check-up to screen women for these predictors of future postpartum depression and possibly to avert the development of a clinically significant depressive episode.

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SUMMARYPurpose: To characterize patterns and determinants of normal and abnormal cognitive development in children with new onset epilepsy compared to healthy controls. Methods: Longitudinal (2-year) cognitive growth was examined in 100 children, age 8-18 years, including healthy controls (n ¼ 48) and children with new onset epilepsy (n ¼ 52). Cognitive maturation was examined as a function of the presence/ absence of two neurobehavioral comorbitiies (attention deficit hyperactivity disorder and/or academic problems) identified at the time of epilepsy diagnosis. Groups were compared across a comprehensive neuropsychological battery assessing intelligence, academic achievement, language, memory, executive function, and psychomotor speed. Results: Children with new onset epilepsy without neurobehavioral comorbidities were comparable to healthy controls at baseline, rate of cognitive development, and follow-up assessment across all neuropsychological domains. In contrast, the presence of neurobehavioral comorbidities was associated with significantly worse baseline and prospective cognitive trajectories across all cognitive domains, especially executive functions. Conclusion: The presence of neurobehavioral comorbidities at the time of epilepsy onset is a major marker of abnormal cognitive development both prior to and after the onset of epilepsy.