Faculty Bibliography

Objectives: Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptakeinhibitor, achieves stable plasma concentrationsover 24 hours with once-daily dosing. This studyevaluated dasotraline in children aged 6-12 years(NCT02428088).
METHOD(S): Patients were randomized 1:1:1 to 6 weeks ofonce-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo.The primary efficacy endpoint was change from baseline(CFB) at Week 6 in ADHD Rating Scale Version IV-HomeVersion (ADHD RS-IV HV) total score, using a mixed modelfor repeated measures (MMRM) in the intent-to-treat (ITT)population. Secondary endpoints included Clinical GlobalImpression-Severity (CGI-S) score and safety endpoints.
RESULT(S): The mean age of 342 randomized patients was9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% ofpatients completed the study. In the ITT population(N = 336), ADHD RS-IV HV total score improvedsignificantly with dasotraline 4 mg/day vs placebo(leastsquares [LS] mean [SE] CFB at Week 6:-17.53 [+/- 1.31]vs-11.36 [+/- 1.29], respectively, p < 0.001; effect size[ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/dayvs placebo at Week 6 (p = 0.001, p = 0.003, respectively).Improvement in CGI-S score was statistically significantwith dasotraline 4 mg/day vs placebo(LS mean [SE] CFBat Week 6:-1.39 [+/- 0.12] vs-1.04 [+/- 0.12], respectively,p = 0.040; ES: 0.29). No significant improvement wasobserved on the ADHD RS-IV HV total score and theCGI-S score for dasotraline 2 mg/day vs placebo. Themost frequent treatment-emergent AEs (=5% and higherthan placebo) were (2 mg/day; 4 mg/day; placebo):insomnia (15.3%; 21.7%; 4.3%, all terms combined),decreased appetite (12.6%; 21.7%; 5.2%), weight loss(5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%),nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%;5.2%; 2.6%).
CONCLUSION(S): Compared with placebo, dasotraline4 mg/day significantly improved ADHD symptoms inchildren, as assessed by ADHD RS-IV HV total score andinattentiveness and hyperactivity/impulsivity subscalescores. Dasotraline was generally well tolerated; mostcommon AEs were insomnia, decreased appetite, weightloss and irritability

BACKGROUND:Oxytocin is a peptide hormone that influences the integration of social cognition with behavior and affect regulation. Oxytocin also prominently directs the transition of neuronal GABA neurotransmission from excitatory to inhibitory after birth. The oxytocin receptor (OXTR) is linked to schizophrenia, a heterogeneous syndrome. Relationships of OXTR polymorphisms with specific clinical features could aid in evaluating any role of oxytocin in the pathogenesis of schizophrenia. METHOD/METHODS:Schizophrenia cases with rare missense coding OXTR single nucleotide variants (SNVs) were identified from a well-characterized sample of cases and controls who were assessed for symptoms, cognition and early life trauma. RESULTS:Five of 48 cases showed rare OXTR variants. Compared to the other cases they had less severe negative symptoms (deficits in emotional expression and motivation) and less severe general psychopathology scores (depression and anxiety). They demonstrated lower nonverbal (performance) than verbal intelligence due to deficient perceptual organization and slow processing speed. They also reported greater early trauma exposure (physical and sexual abuse and emotional trauma). CONCLUSION/CONCLUSIONS:Cases carrying rare OXTR SNVs had less negative and affective symptoms than other cases, but similar psychotic symptoms, along with specific cognitive deficits. The clinical characterization of these cases occurred in association with environmental exposure to early trauma, especially sexual abuse, which may have influenced the expression of schizophrenia in subjects harboring specific SNVs in the OXTR.

Classical trigeminal neuralgia (TN) is a specific type of neuropathic orofacial pain of which the plasticity of brain structure and connectivity have remained largely unknown. A total of 62 TN patients were included and referred to MRI scans. Voxel-based morphometry was used to analyze the change of gray matter volume. Resting-state functional imaging was used to analyze the connectivity between brain regions. The results showed gray matter volume reduction in components of the prefrontal cortex, precentral gyrus, cerebellar tonsil, thalamus, hypothalamus, and nucleus accumbens among right TN patient and in the inferior frontal gyrus, precentral gyrus, cerebellum, thalamus, ventral striatum, and putamen among left TN patients. The connections between the right superior frontal gyrus and right middle frontal gyrus were lower in right TN patients. The connection between the left precentral gyrus and the left superior frontal gyrus was lower while the connection between bilateral thalamus was higher in left TN patients. The changes of volume in bilateral thalamus of right TN patients and left ventral striatum of left TN patients, and the connectivity between bilateral thalamus of left TN patients were moderately correlated with pain duration. These findings suggest that brain regions such as the thalamus may not only be involved in processing of pain stimuli but also be important for the development of TN. The left hemisphere may be dominant in processing and modulation of TN pain signal. Chronification of TN induces volume changes in brain regions which are associated with emotional or cognitive modulation of pain. Hum Brain Mapp 39:609-621, 2018. © 2017 Wiley Periodicals, Inc.

OBJECTIVE:Exercise-induced wheeze (EIW) has been found to be associated with asthma-related urgent care in school-aged children. Despite asthma's high prevalence and morbidity among adolescents, this association has not been examined in adolescents. We tested the association of EIW and other asthma symptoms to asthma-related ED visits and hospitalizations in urban adolescents with probable asthma. We hypothesized that EIW would be associated with urgent care. METHODS:In this cross-sectional study 30,467 high school students (mean age = 16.0) from 49 NYC schools completed two brief validated measures, one assessing probable asthma and the other the frequency of six asthma symptoms over the past year. Adolescents also reported if in the past year they had an asthma-related ED visit or hospitalization. Analyses presented here included students with probable asthma (n = 9149). Using logistic regression, we modeled each asthma symptom as a function of ED visits and hospitalizations adjusting for sex, age, race/ethnicity and asthma severity. Multivariable models included all symptoms to account for the potential interaction between symptoms. RESULTS:Among adolescents with probable asthma, EIW was associated with ED visits and hospitalizations. In multivariable models wheeze without a cold, chest tightness, night wakening, but not EIW, were significantly associated with both ED visits and hospitalizations. CONCLUSIONS:Unlike findings with younger children, EIW does not appear to be associated with ED visits and hospitalizations among urban adolescents with probable asthma. Instead, symptoms, such as chest tightness and night wakening, appear to be important at identifying adolescents at risk for asthma-related urgent care.

OBJECTIVE:CD16+ /CD163+ macrophages (MΦ)s and microglia accumulate in the brains of patients with HIV encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders (HAND), HIV-associated dementia (HIV-D). Recently, we found that some parenchymal microglia in brain of HIV+ subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE, HIV/noE, and HIV- controls. METHODS:Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163+ , CD16+ or CD68+ MΦs/microglia per case, using terminal continuation (TC) RNA amplification and a custom-designed array platform. RESULTS:Several classes of microglial transcripts in HIVE and HIV/noE, were altered, relative to HIV- subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors are reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE. INTERPRETATION/CONCLUSIONS:Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as ascertain alterations in specific pathways, genes, and, ostensibly, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain.

Dengue is the most common arboviral infection of humans, responsible for a substantial disease burden across the tropics. Traditional insecticide-based vector-control programmes have limited effectiveness, and the one licensed vaccine has a complex and imperfect efficacy profile. Strains of the bacterium Wolbachia, deliberately introduced into Aedes aegyptimosquitoes, have been shown to be able to spread to high frequencies in mosquito populations in release trials, and mosquitoes infected with these strains show markedly reduced vector competence. Thus, Wolbachia represents an exciting potential new form of biocontrol for arboviral diseases, including dengue. Here, we review how mathematical models give insight into the dynamics of the spread of Wolbachia, the potential impact of Wolbachia on dengue transmission, and we discuss the remaining challenges in evaluation and development.

This study investigated the clinical utility of the Achenbach System of Empirically Based Assessment (ASEBA) for identifying youth at risk for suicide. Specifically, we investigated how well the Total Problems scores and the sum of two suicide-related items (#18 "Deliberately harms self or attempts suicide" and #91 "Talks about killing self") were able to distinguish youth with a history of suicidal behavior. Youth (N = 1117) aged 5-18 were recruited for two studies of mental illness. History of suicidal behavior was assessed by semi-structured interviews (K-SADS) with youth and caregivers. Youth, caregivers, and a primary teacher each completed the appropriate form (YSR, CBCL, and TRF, respectively) of the ASEBA. Areas under the curve (AUCs) from ROC analyses and diagnostic likelihood ratios (DLRs) were used to measure the ability of both Total Problems T scores, as well as the summed score of two suicide-related items, to identify youth with a history of suicidal behavior. The Suicide Items from the CBCL and YSR performed well (AUCs = 0.85 and 0.70, respectively). The TRF Suicide Items did not perform better than chance, AUC = 0.45. The AUCs for the Total Problems scores were poor-to-fair (0.33-0.65). The CBCL Suicide Items outperformed all other scores (ps = 0.04 to <0.0005). Combining the CBCL and YSR items did not lead to incremental improvement in prediction over the CBCL alone. The sum of two questions from a commonly used assessment tool can offer important information about a youth's risk for suicidal behavior. The low burden of this approach could facilitate wide-spread screening for suicide in an increasingly at-risk population.