The Child Opportunity Index 2.0 and Disparities in Pediatric Cardiorespiratory Fitness.

OBJECTIVE: To evaluate the effect of neighborhood-level characteristics on cardiorespiratory fitness (CRF) via peak oxygen consumption (VO2peak) for healthy pediatric patients. STUDY DESIGN: The institutional cardiopulmonary exercise testing (CPET) database was analyzed retrospectively. All patients aged ≤ 18 years without a diagnosis of cardiac disease and with a maximal effort CPET were included. Patients were divided into three self-identified racial categories: White, Black, and Latinx. The Child Opportunity Index (COI) 2.0 was used to analyze social determinants of health. CRF was evaluated based on COI quintiles and race. Assessment of the effect of COI on racial disparities in CRF was performed using ANCOVA. RESULTS: A total of 1753 CPETs met inclusion criteria. The mean VO2peak was 42.1 ± 9.8 mL/kg/min. The VO2peak increased from 39.1 ± 9.6 mL/kg/min for patients in the very low opportunity cohort to 43.9 ± 9.4 mL/kg/min for patients in the very high opportunity cohort. White patients had higher percent predicted VO2peak compared with both Black and Latinx patients (P < .01 for both comparisons). The racial differences in CRF were no longer significant when adjusting for COI. CONCLUSION: In a large pediatric cohort, COI was associated with CRF. Racial disparities in CRF are reduced when accounting for modifiable risk factors.

Auditory Processing Differences in Toddlers With Autism Spectrum Disorder.

Purpose Auditory processing measures have been used in an attempt to understand the relationship between neurological mechanisms and autism spectrum disorder (ASD) symptomatology in school-age children. The focus of the current study was to understand neural auditory processing in 2- to 3-year-olds with ASD. Method Auditory processing measures (click auditory brainstem responses and speech-evoked frequency-following responses) were hypothesized to differ between typically developing children (n = 18) and children with ASD (n = 18). Auditory processing measures were hypothesized to relate to language development in children with ASD. Results The current study found limited differences in auditory processing measures between the two groups. No relationships were found between auditory processing measures and language development measures. Conclusions Future research is necessary to characterize auditory processing in toddlers with ASD. Longitudinal approaches should be considered when studying auditory processing in children with ASD in order to explore its developmental relationship with ASD symptomatology.

A retrospective survival analysis of Glioblastoma patients treated with selective serotonin reuptake inhibitors.

Glioblastoma (GBM) is the most common and aggressive form of malignant glioma in adults with a median overall survival (OS) time of 16-18 months and a median age of diagnosis at 64 years old. Recent work has suggested that depression and psychosocial distress are associated with worse outcomes in patients with GBM. We therefore hypothesized that the targeted neutralization of psychosocial distress with selective serotonin reuptake inhibitor (SSRI) antidepressant treatment would be associated with a longer OS among patients with GBM. To address this hypothesis, we retrospectively studied the association between adjuvant SSRI usage and OS in GBM patients treated by Northwestern Medicine-affiliated providers. The medical records of 497 GBM patients were analyzed after extraction from the Northwestern Medicine Enterprise Data Warehouse. Data were retrospectively studied using a multivariable Cox model with SSRI use defined as a time-dependent variable for estimating the association with OS. Of the 497 patients, 315 individuals died, while 182 were censored due to the loss of follow-up or were alive at the end of our study. Of the 497 patients, 151 had a recorded use of SSRI treatment during the disease course. Unexpectedly, SSRI usage was not associated with an OS effect in both naïve (HR = 0.81, 95% CI = 0.64-1.03) and adjusted time-dependent (HR = 1.26, 95% CI = 0.97-1.63) Cox models. Ultimately, we failed to find an association between SSRI treatment and an improved OS of patients with GBM. Additional work is necessary for understanding the potential therapeutic effects of SSRIs when combined with other treatment approaches, and immunotherapies in particular, for subjects with GBM.

Stable auditory processing underlies phonological awareness in typically developing preschoolers.

Sound processing is an important scaffold for early language acquisition. Here we investigate its relationship to three components of phonological processing in young children (∼age 3): Phonological Awareness (PA), Phonological Memory (PM), and Rapid Automatized Naming (RAN). While PA is believed to hinge upon consistency of sound processing to distinguish and manipulate word features, PM relies on an internal store of the sounds of language and RAN relies on fluid production of those sounds. Given the previously demonstrated link between PA and the auditory system, we hypothesized that only this component would be associated with auditory neural stability. Moreover, we expected relationships to manifest at early ages because additional factors may temper the association in older children. We measured across-trial stability of the frequency-following response, PA, PM, and RAN longitudinally in twenty-seven children. Auditory neural stability at age ∼3 years exclusively predicts PA, but this relationship vanishes in older children.

The interplay among psychological distress, the immune system, and brain tumor patient outcomes.

A malignant brain tumor diagnosis is often accompanied with intense feelings and can be associated with psychosocial conditions including depression, anxiety, and/or increased distress levels. Previous work has highlighted the impact of uncontrolled psychological distress among brain tumor patients. Given the negative impact of maladaptive psychosocial and biobehavioral factors on normal immune system functions, the question remains as to how psychological conditions potentially affect the brain tumor patient anti-tumor immune response. Since immunotherapy has yet to show efficacy at increasing malignant glioma patient survival in all randomized, phase III clinical trials to-date, this review provides new insights into the potential negative effects of chronic distress on brain tumor patient immune functions and outcomes.

The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma.

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16-21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experimental brain tumor model. Given the recent phase III clinical success of immunotherapy in patients with many types of cancer, but not for patients with GBM, we hypothesize that aging enhances immunosuppression in the brain and contributes to the lack of efficacy for immunotherapy to improve mOS in patients with malignant glioma. Herein, we compare epidemiological data for the incidence and mortality of patients with central nervous system (CNS) cancers, in addition to immune-related gene expression in the normal human brain, as well as peripheral blood immunological changes across the adult lifespan. Methods: Data were extracted from the National Cancer Institute's surveillance, epidemiology, and end results (SEER)-, the Broad Institute's Genotype Tissue Expression project (GTEx)-, and the University of California San Francisco's 10k Immunomes-databases and analyzed for associations with aging. Results: The proportion of elderly individuals, defined as ≥65 years of age, has predominantly increased for more than 100 years in the United States. Over time, the rise in elderly United States citizens has correlated with an increased incidence and mortality rate associated with primary brain and other CNS cancer. With advanced aging, human mRNA expression for factors associated with immunoregulation including immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO) and programmed death-ligand 1 (PD-L1), as well as the dendritic cell surface marker, CD11c, increase in the brain of normal human subjects, coincident with increased circulating immunosuppressive Tregs and decreased cytolytic CD8+ T cells in the peripheral blood. Strikingly, these changes are maximally pronounced in the 60-69 year old group; consistent with the median age of a diagnosis for GBM. Conclusion: These data demonstrate a significant association between normal human aging and increased immunosuppression in the circulation and CNS; particularly late in life. Our data raise several hypotheses including that, aging: (i) progressively suppresses normal immunosurveillance and thereby contributes to GBM cell initiation and/or outgrowth; (ii) decreases immunotherapeutic efficacy against malignant glioma.

Children with autism spectrum disorder have unstable neural responses to sound.

Autism spectrum disorder (ASD) is diverse, manifesting in a wide array of phenotypes. However, a consistent theme is reduced communicative and social abilities. Auditory processing deficits have been shown in individuals with ASD-these deficits may play a role in the communication difficulties ASD individuals experience. Specifically, children with ASD have delayed neural timing and poorer tracking of a changing pitch relative to their typically developing peers. Given that accurate processing of sound requires highly coordinated and consistent neural activity, we hypothesized that these auditory processing deficits stem from a failure to respond to sound in a consistent manner. Therefore, we predicted that individuals with ASD have reduced neural stability in response to sound. We recorded the frequency-following response (FFR), an evoked response that mirrors the acoustic features of its stimulus, of high-functioning children with ASD age 7-13 years. Evident across multiple speech stimuli, children with ASD have less stable FFRs to speech sounds relative to their typically developing peers. This reduced auditory stability could contribute to the language and communication profiles observed in individuals with ASD.

The neural legacy of a single concussion.

It has been hypothesized that concussions impart lasting brain damage, even after a patient has ostensibly recovered. This hypothesis is based largely upon neuropathological studies in deceased athletes, however, leaving open the question of whether it can be detected in vivo. We measured neural responses to speech in collegiate student-athletes with a history of a single concussion from which they had recovered. These student-athletes had weaker responses to speech than age- and position-matched peers. This group difference suggests that concussions engender small, but detectable, changes in brain function prior to the emergence of frank behavioral indications.

Individual differences in speech-in-noise perception parallel neural speech processing and attention in preschoolers.

From bustling classrooms to unruly lunchrooms, school settings are noisy. To learn effectively in the unwelcome company of numerous distractions, children must clearly perceive speech in noise. In older children and adults, speech-in-noise perception is supported by sensory and cognitive processes, but the correlates underlying this critical listening skill in young children (3-5 year olds) remain undetermined. Employing a longitudinal design (two evaluations separated by ∼12 months), we followed a cohort of 59 preschoolers, ages 3.0-4.9, assessing word-in-noise perception, cognitive abilities (intelligence, short-term memory, attention), and neural responses to speech. Results reveal changes in word-in-noise perception parallel changes in processing of the fundamental frequency (F0), an acoustic cue known for playing a role central to speaker identification and auditory scene analysis. Four unique developmental trajectories (speech-in-noise perception groups) confirm this relationship, in that improvements and declines in word-in-noise perception couple with enhancements and diminishments of F0 encoding, respectively. Improvements in word-in-noise perception also pair with gains in attention. Word-in-noise perception does not relate to strength of neural harmonic representation or short-term memory. These findings reinforce previously-reported roles of F0 and attention in hearing speech in noise in older children and adults, and extend this relationship to preschool children.

Factors Influencing Short-term Synaptic Plasticity in the Avian Cochlear Nucleus Magnocellularis.

Defined as reduced neural responses during high rates of activity, synaptic depression is a form of short-term plasticity important for the temporal filtering of sound. In the avian cochlear nucleus magnocellularis (NM), an auditory brainstem structure, mechanisms regulating short-term synaptic depression include pre-, post-, and extrasynaptic factors. Using varied paired-pulse stimulus intervals, we found that the time course of synaptic depression lasts up to four seconds at late-developing NM synapses. Synaptic depression was largely reliant on exogenous Ca(2+)-dependent probability of presynaptic neurotransmitter release, and to a lesser extent, on the desensitization of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPA-R). Interestingly, although extrasynaptic glutamate clearance did not play a significant role in regulating synaptic depression, blocking glutamate clearance at early-developing synapses altered synaptic dynamics, changing responses from depression to facilitation. These results suggest a developmental shift in the relative reliance on pre-, post-, and extrasynaptic factors in regulating short-term synaptic plasticity in NM.