Faculty Bibliography

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2022 articles that we think deserve your attention or at least a second read.

INTRODUCTION/UNASSIGNED:Agitation in children and adolescents in the emergency department (ED) can be dangerous and distressing for patients, family and staff. We present consensus guidelines for management of agitation among pediatric patients in the ED, including non-pharmacologic methods and the use of immediate and as-needed medications. METHODS/UNASSIGNED:Using the Delphi method of consensus, a workgroup comprised of 17 experts in emergency child and adolescent psychiatry and psychopharmacology from the the American Association for Emergency Psychiatry and the American Academy of Child and Adolescent Psychiatry Emergency Child Psychiatry Committee sought to create consensus guidelines for the management of acute agitation in children and adolescents in the ED. RESULTS/UNASSIGNED:Consensus found that there should be a multimodal approach to managing agitation in the ED, and that etiology of agitation should drive choice of treatment. We describe general and specific recommendations for medication use. CONCLUSION/UNASSIGNED:, with permission from the authors. Copyright © 2019.

AIM/OBJECTIVE:To conduct the first systematic review and meta-analysis assessing whether attention-deficit/hyperactivity disorder (ADHD) is associated with disorders of the eye, and/or altered measures of visual function. METHOD/METHODS:Based on a pre-registered protocol (PROSPERO: CRD42021256352), we searched PubMed, Web of Knowledge/Science, Ovid Medline, Embase and APA PsycINFO up to 16th November 2021, with no language/type of document restrictions. We included observational studies reporting at least one measure of vision in people of any age meeting DSM/ICD criteria for ADHD and in people without ADHD; or the prevalence of ADHD in people with and without vision disorders. Study quality was assessed with the Appraisal tool for Cross-Sectional Studies (AXIS). Random effects meta-analyses were used for data synthesis. RESULTS:We included 42 studies in the narrative synthesis and 35 studies in the meta-analyses (3,250,905 participants). We found meta-analytic evidence of increased risk of astigmatism (OR = 1.79 [CI: 1.50, 2.14]), hyperopia and hypermetropia (OR = 1.79 [CI: 1.66, 1.94]), strabismus (OR = 1.93 [CI: 1.75, 2.12]), unspecified vision problems (OR = 1.94 [CI: 1.38, 2.73]) and reduced near point of convergence (OR = 5.02 [CI: 1.78, 14.11]); increased lag (Hedge's g = 0.63 [CI: 0.30, 0.96]) and variability (Hedge's g = 0.40 [CI: 0.17, 0.64]) of the accommodative response; and increased self-reported vision problems (Hedge's g = 0.63 [CI: 0.44, 0.82]) in people with ADHD compared to those without ADHD (with no significant heterogeneity). We also found meta-analytic evidence of no differences between people with and without ADHD on retinal nerve fiber layer thickness (Hedge's g = -0.19 [CI: -0.41, 0.02]) and refractive error (Hedge's g = 0.08 [CI: -0.26, 0.42]) (with no significant heterogeneity). DISCUSSION/CONCLUSIONS:ADHD is associated with some self-reported and objectively ascertained functional vision problems, but not with structural alterations of the eye. Further studies should clarify the causal relationship, if any, between ADHD and problems of vision. TRIAL REGISTRATION/BACKGROUND:PROSPERO registration: CRD42021256352.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection.
Method(s): Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections.
Result(s): Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections.
Conclusion(s): We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.
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Neuroscience has a long history of investigating the neural correlates of brain functions. One example is fear, which has been studied intensely in a variety of species. In parallel, unease about definitions of brain functions has existed for over 100 years. Because the translational impact of basic research hinges on how we define these functions, these definitions should be carefully considered.

OBJECTIVE:To test the hypothesis that high frequency oscillations (HFOs) between 250 and 500Hz occur in mouse models of Alzheimer's disease (AD) and thus are not unique to epilepsy. METHODS:Experiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock-out (PS2KO) mice, and the Ts65Dn model of Down's syndrome. We recorded HFOs using wideband (0.1-500Hz, 2kHz) intra-hippocampal and cortical surface EEG at 1month until 24months-old during wakefulness, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Interictal spikes (IIS) and seizures were also analyzed for the possible presence of HFOs. Comparisons were made to the intra-hippocampal kainic acid and pilocarpine models of epilepsy. RESULTS:We describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1month of age and prior to amyloid-β plaque neuropathology. HFOs were most frequent during SWS (vs. REM or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IIS and seizures in the AD models, although with altered spectral properties compared to isolated HFOs. SIGNIFICANCE/CONCLUSIONS:Our data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker which is detectable from the scalp and thus amenable to non-invasive detection in people at risk for AD.

OBJECTIVES/OBJECTIVE:The KNee OsteoArthritis Prediction (KNOAP2020) challenge was organized to objectively compare methods for the prediction of incident symptomatic radiographic knee osteoarthritis within 78 months on a test set with blinded ground truth. DESIGN/METHODS:The challenge participants were free to use any available data sources to train their models. A test set of 423 knees from the Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study consisting of magnetic resonance imaging (MRI) and X-ray image data along with clinical risk factors at baseline was made available to all challenge participants. The ground truth outcomes, i.e., which knees developed incident symptomatic radiographic knee osteoarthritis (according to the combined ACR criteria) within 78 months, were not provided to the participants. To assess the performance of the submitted models, we used the area under the receiver operating characteristic curve (ROCAUC) and balanced accuracy (BACC). RESULTS:Seven teams submitted 23 entries in total. A majority of the algorithms were trained on data from the Osteoarthritis Initiative. The model with the highest ROCAUC (0.64 (95% confidence interval (CI): 0.57-0.70)) used deep learning to extract information from X-ray images combined with clinical variables. The model with the highest BACC (0.59 (95% CI: 0.52-0.65)) ensembled three different models that used automatically extracted X-ray and MRI features along with clinical variables. CONCLUSION/CONCLUSIONS:The KNOAP2020 challenge established a benchmark for predicting incident symptomatic radiographic knee osteoarthritis. Accurate prediction of incident symptomatic radiographic knee osteoarthritis is a complex and still unsolved problem requiring additional investigation.

Currently, pediatric research involving investigational gene therapies (GT, used without intending to imply a therapeutic effect) targets a broad range of indications (including rare and ultra-rare diseases) that vary in severity and availability of approved disease-modifying therapies. Because of this diversity of circumstances, there is no one-size-fits-all list of ethical concerns relevant to all uses of investigational GTs in children. Here, we review the main ethical issues, specifically those surrounding the current state of knowledge about GT product-related immunogenicity, toxicity, duration, irreversibility, informed consent/assent, trial design (including the question of who 'goes first'), participant and caregiver burdens, and equity in diagnosis and access to research opportunities. Ethical issues that can be anticipated to arise in pediatric GT clinical trials, e.g., the uncertainty and risk of this research, the resultant preclusion of GT trial participants from other research, the length of follow-up monitoring, and the urgency often felt by caregivers dealing with dire, rapidly progressive conditions, should be proactively identified, addressed in accordance with existing best practices, and transparently discussed among all stakeholders.

BACKGROUND:Prenatal smoking and drinking are associated with sudden infant death syndrome and neurodevelopmental disorders. Infants with these outcomes also have altered autonomic nervous system (ANS) regulation. We examined the effects of prenatal smoking and drinking on newborn ANS function. METHODS:Pregnant women were enrolled in Northern Plains, USA (NP) and Cape Town (CT), South Africa. Daily drinking and weekly smoking data were collected prenatally. Physiological measures were obtained during sleep 12-96 h post-delivery. RESULTS:In all, 2913 infants from NP and 4072 from CT were included. In active sleep, newborns of mothers who smoked throughout pregnancy, compared to non-smokers, had higher breathing rates (2.2 breaths/min; 95% CI: 0.95, 3.49). Quit-early smoking was associated with reductions in beat-to-beat heart rate variability (HRV) in active (-0.08 s) and quiet sleep (-0.11 s) in CT. In girls, moderate-high continuous smoking was associated with increased systolic (3.0 mmHg, CI: 0.70, 5.24) and diastolic blood pressure (2.9 mmHg, CI: 0.72, 5.02). In quiet sleep, low-continuous drinking was associated with slower heart rate (-4.5 beat/min). In boys, low-continuous drinking was associated with a reduced ratio of low-to-high frequency HRV (-0.11, CI: -0.21, -0.02). CONCLUSIONS:These findings highlight potential ANS pathways through which prenatal drinking and smoking may contribute to neurodevelopment outcomes. IMPACT/CONCLUSIONS:In this prospective cohort study of 6985 mother-infant dyads prenatal drinking and smoking were associated with multiple ANS parameters. Smoking was associated with increased neonatal breathing rates among all infants, and heart rate variability (HRV) and blood pressure (BP) among girls. Drinking was associated with reductions in HR and BP among all newborns, and reductions in the ratio of low to-high frequency HRV among boys. These findings suggest that prenatal smoking and drinking alter newborn ANS which may presage future neurodevelopmental disorders.

Agitated patients can be dangerous to themselves and others. In fact, severe medical complications and death can occur with severe agitation. Because of this, agitation is considered a medical and psychiatric emergency. Regardless of the treatment setting, identifying the agitated patient early is a necessary skill. The authors review relevant literature regarding the identification and management of agitation and summarize current recommendations for adults, as well as children and adolescents.