Faculty Bibliography

IMPORTANCE:Recent studies have identified characteristic symptom patterns of long COVID (LC) in adults and children older than 5 years. However, LC remains poorly characterized in early childhood. This knowledge gap limits efforts to identify, care for, and prevent LC in this vulnerable population. OBJECTIVES:To identify symptoms that had the greatest difference in frequency comparing children with a history of SARS-CoV-2 infection to those without, to identify differences in the types of symptoms by age group (infants/toddlers [0-2 years] vs preschool-aged children [3-5 years]), and to derive an index that can be used in research studies to identify young children with LC. DESIGN, SETTING, AND PARTICIPANTS:This was a multisite longitudinal cohort study with enrollment from over 30 US health care and community settings, including infants, toddlers, and preschool-aged children with and without SARS-CoV-2 infection history. Study data were analyzed from May to December 2024. EXPOSURE:SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES:LC and 41 symptoms among infants/toddlers and 75 symptoms among preschool-aged children. RESULTS:The study included 472 infants/toddlers (mean [SD] age, 12 [9] months; 278 infected with SARS-CoV-2; 194 uninfected; 234 male [50%]; 73 Black or African American [16%]; 198 Hispanic, Latino, or Spanish [43%]; 242 White [52%]) and 539 preschool-aged children (mean [SD] age, 48 [10] months; 399 infected with SARS-CoV-2; 140 uninfected; 277 female [51%]; 70 Black or African American [13%]; 210 Hispanic, Latino, or Spanish [39%]; 287 White [54%]). The median (IQR) time between first infections and completion of symptom surveys was 318 (198-494) days for infants/toddlers and 520 (330-844) days for preschool-aged children. A research index was derived for each age group based on symptoms most associated with infection history. The index is calculated by summing scores assigned to each prolonged symptom that was present, where higher scores indicate greater magnitude of association with history of SARS-CoV-2 infection: poor appetite (5 points), trouble sleeping (3.5 points), wet cough (3.5 points), dry cough (3 points), and stuffy nose (0.5 points) for infants/toddlers, and daytime tiredness/sleepiness/low energy (6.5 points) and dry cough (3 points) for preschool-aged children. Among infants/toddlers with infection, 40 of 278 (14%) were classified as having probable LC by having an index of at least 4 points. Among preschool-aged children, 61 of 399 (15%) were classified as having probable LC by having an index of at least 3 points. Participants with higher indices often had poorer overall health, lower quality of life, and perceived delays in developmental milestones. CONCLUSIONS AND RELEVANCE:This cohort study identified symptom patterns and derived research indices that were distinct between the 2 age groups and differed from those previously identified in older ages, demonstrating the need to characterize LC separately across age ranges.

This study examined biopsychosocial factors associated with the use of intramuscular (IM) agitation emergency medication in child and adolescent psychiatric inpatients. A retrospective review of 1,101 patients hospitalized between June 2018-November 2021 at an urban teaching hospital identified predictors of IM medication use through linear regression analysis. Among these patients, 196 received IM medication during their stay. Female sex was associated with a lower likelihood of receiving IM treatment, while factors such as prior involvement with child protective services, a history of violence, previous psychiatric hospitalizations, and use of multiple home psychiatric medications increased the likelihood. Agitation episodes pose risks to both patients and staff, underscoring the importance of early identification and intervention. Understanding these risk factors may guide proactive strategies to reduce the frequency and severity of agitation and limit reliance on emergency pharmacological interventions. Further research is needed to refine predictive models and explore non-pharmacological management approaches.

BACKGROUND:Hyperexcitability in Alzheimer's disease (AD) is proposed to emerge early and contribute to disease progression. The dentate gyrus (DG) and its primary cell type, granule cells (GCs) are implicated in hyperexcitability in AD. Hence, we hypothesized that mossy cells (MCs), important regulators of GC excitability, contribute to early hyperexcitability in AD. Indeed, MCs and GCs are linked to hyperexcitability in epilepsy. METHODS:Using the Tg2576 model of AD and WT mice (~ 1 month-old), we compared MCs and GCs electrophysiologically and morphologically, assessed the activity marker c-Fos, Aβ expression and a hippocampal- and MC-dependent memory task that is impaired at 3-4 months of age in Tg2576 mice. RESULTS:Tg2576 MCs had increased spontaneous excitatory events (sEPSP/Cs) and decreased spontaneous inhibitory currents (sIPSCs), increasing the excitation/inhibition ratio. Additionally, Tg2576 MC intrinsic excitability was enhanced. Consistent with in vitro results, Tg2576 MCs showed enhanced c-Fos protein expression. Tg2576 MCs had increased intracellular Aβ expression, suggesting a reason for increased excitability. GCs showed increased excitatory and inhibitory input without changes in intrinsic properties, consistent with effects of increased MC activity. In support, increased GC activity was normalized by an antagonist of MC input to GCs. Also in support, Tg2576 MC axons showed sprouting to the area of GC dendrites. These effects occurred before an impairment in the memory task, suggesting they are extremely early alterations. CONCLUSIONS:Alterations in Tg2576 MCs and GCs early in life suggest an early role for MCs in increased GC excitability. MCs may be a novel target to intervene in AD pathophysiology at early stages.

Parental support and acceptance are strong protective factors for better mental health outcomes among transgender and gender diverse youth. Psychological inflexibility, specifically in the role of parenting, or "parenting inflexibility", refers to an over-reliance on avoidance strategies at the expense of parenting values. Parenting inflexibility may be related to parental support, making it a useful target of intervention for parents of transgender youth. The aim of the present study was to develop a brief clinically useful measure of parenting inflexibility based on a synthesis of existing measures and to evaluate the psychometric properties across two study populations. Study 1 used exploratory factor analysis to examine this measure among parents in the general population recruited using MTurk. Study 2 used confirmatory factor analysis to examine the measure among parents of transgender youth recruited from a clinic. The final measure, the Impact of Parenting Avoidance (IPA) scale, is a one-factor 7-item measure of parenting inflexibility that is easy to administer and interpret in a pediatric health setting. The resulting measure demonstrated acceptable reliability, and it was significantly correlated with important outcome variables, such as negative parenting practices and lower perceived parental support among transgender and gender diverse youth.

UNLABELLED:Research supports an association between diet and health, and emerging evidence suggests that diet is associated with neuropsychiatric symptoms. However, no human study has examined an anti-inflammatory diet across rigorously defined psychiatric diagnoses and its associations with symptom severity and cognition. As inflammation is implicated in mental illness, we investigated adherence to the Mediterranean diet (MD), an anti-inflammatory diet, and the standard American diet (SAD), and examined cross-sectional relationships with psychiatric symptoms and cognition. METHOD/METHODS:Participants included 54 individuals with psychotic disorders, 30 with non-psychosis affective disorders and 40 healthy controls. Participants underwent diagnostic interviews, PANSS symptom ratings, and MATRICS cognitive assessments. The self-report GBAQ was used to assess adherence to the MD versus SAD. RESULTS:The psychosis group was significantly more likely to consume the SAD than healthy controls (p = 0.007), with MD adherence predicting better working memory (r = 0.461, p < 0.001). In the non-psychosis affective disorders group, MD adherence predicted slower processing speed (r = -0.376, p = 0.049). In the non-psychosis affective disorders group, MD predicted reduced PANSS General Psychopathology scale (r = -0.449, p = 0.013), as well as the Activation (r = -0.362, p = 0.049), and Dysphoric Mood factors (r = -0.403, p = 0.027). DISCUSSION/CONCLUSIONS:This first-of-its kind study identified poor dietary choices in persons with psychosis, showing significantly lower symptoms and better cognition in association with the MD in transdiagnostic analyses. It supports the study of dietary interventions for prevention and treatment of psychiatric conditions.

IMPORTANCE/UNASSIGNED:Expectancy effects are significant confounding factors in psychiatric randomized clinical trials (RCTs), potentially affecting the interpretation of study results. This narrative review is the first, to our knowledge, to explore the relationship between expectancy effects, compromised blinding integrity, and the effects of active treatment/placebo in psychiatric RCTs. Additionally, we present statistical and experimental approaches that may help mitigate the confounding impact of expectancy effects. The review concludes with recommendations to enhance the reliability of RCTs in psychiatry. OBSERVATIONS/UNASSIGNED:The placebo response comprises both specific and nonspecific elements, with expectation being a key specific component. Evidence from experimental and clinical studies suggests that expectancy can influence treatment responses in RCTs. Blinding integrity may be compromised by perceived treatment efficacy and adverse effects, introducing bias into outcome assessments. Treatment expectations can lead to unblinding during RCTs, and meta-analytic data from studies in the fields of psychedelics and anxiety disorders indicate that this can influence effect sizes. Therefore, controlling for expectancy effects is essential when interpreting RCT results. Novel statistical methods, though still in need of further validation, offer strategies to address this issue. Another approach may involve experimental medicine models, which aim to develop objective improvement markers (readouts) less affected by expectancy effects. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Expectancy effects represent a significant confound in psychiatric RCTs. We recommend collecting data on treatment expectations alongside monitoring blinding integrity to more accurately interpret study results. Additionally, developing objective readouts that are less confounded by expectancy effects offers another promising avenue for mitigating these confounding influences in psychiatric RCTs.

BACKGROUND:Children born preterm are at heightened risk for neurodevelopmental impairment, including specific deficits in attention. Few studies have investigated change over time in attention problems prior to school entry. The current study aims to describe trajectories of attention problems from age 2 through 5 years in a cohort of children born <30 weeks of gestational age (GA), identify sociodemographic, medical, and neurobehavioral characteristics associated with attention trajectories, and test whether attention problem trajectories predict the risk of a reported attention-deficit/hyperactivity disorder (ADHD) diagnosis. METHODS:We studied 608 infants from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study, a prospective, multisite study of infants born <30 weeks of GA. Parents reported on child attention problems at ages 2, 3, 4, and 5 years using the Child Behavior Checklist and the Behavior Assessment System for Children. Sociodemographic and medical characteristics were assessed via maternal interview and medical record review. Neurobehavioral characteristics were determined using neonatal and 2-year assessments. Parent report of child ADHD diagnosis was obtained. We used latent growth curve (LGC) modeling to test our study aims. RESULTS:A linear LGC model provided the best fit to the data. The average trajectory of attention problems evidenced low initial levels of symptoms and little change over time, yet there was significant heterogeneity in both initial levels and change over time. Individual differences in trajectory parameters were associated with sociodemographic, medical, environmental, and neurobehavioral characteristics. Children with higher initial levels of attention problems as well as steeper increases in attention problems over time were more likely to have a reported ADHD diagnosis. CONCLUSIONS:There is significant heterogeneity in trajectories of attention problems from age 2 to 5 in children born <30 weeks of GA and these differences have clinical relevance. These data could inform follow-up guidelines for preterm infants.

BACKGROUND:Concerns about the cardiovascular safety of medications used for the treatment of attention-deficit hyperactivity disorder (ADHD) remain. We aimed to compare the effects of pharmacological treatments for ADHD on haemodynamic values and electrocardiogram (ECG) parameters in children, adolescents, and adults. METHODS:For this systematic review and network meta-analysis, we searched 12 electronic databases, including Cochrane CENTRAL, Embase, PubMed, and the WHO International Clinical Trials Registry Platform, from database inception to Jan 18, 2024, for published and unpublished randomised controlled trials comparing amphetamines, atomoxetine, bupropion, clonidine, guanfacine, lisdexamfetamine, methylphenidate, modafinil, or viloxazine against each other or placebo. Primary outcomes were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), measured in mm Hg, and pulse, measured in beats per minute, at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. Summary data were extracted and pooled in random-effects network meta-analyses. Certainty of evidence was assessed with the Confidence in Network Meta-Analysis (CINeMA) framework. This study was registered with PROSPERO, CRD42021295352. Before study initiation, we contacted representatives of a UK-based charity of people with lived experience of ADHD-the ADHD Foundation-regarding the relevance of the topic and the appropriateness of the outcomes chosen. FINDINGS/RESULTS:102 randomised controlled trials with short-term follow-up (median 7 weeks [IQR 5-9]) were included, encompassing 13 315 children and adolescents (aged ≥5 years and <18 years; mean age 11 years [SD 3]; of available data, 9635 [73%] were male and 3646 [27%] were female; of available data, 289 [2%] were Asian, 1719 [15%] were Black, and 8303 [71%] were White) and 9387 adults (≥18 years, mean age 35 years [11]; of available data, 5064 [57%] were male and 3809 [43%] were female; of available data, 488 [6%] were Asian, 457 [6%] were Black, and 6372 [79%] were White). Amphetamines, atomoxetine, lisdexamfetamine, methylphenidate, and viloxazine led to increments in haemodynamic values in children and adolescents, adults, or both. In children and adolescents, mean increase against placebo ranged from 1·07 (95% CI 0·36-1·79; moderate CINeMA confidence) with atomoxetine to 1·81 (1·05-2·57; moderate) with methylphenidate for SBP; from 1·93 (0·74-3·11; high) with amphetamines to 2·42 (1·69-3·15; low) with methylphenidate for DBP; and from 2·79 (1·05-4·53; moderate) with viloxazine to 5·58 (4·67-6·49; high) with atomoxetine for pulse. In adults, mean increase against placebo ranged from 1·66 (95% CI 0·38-2·93; very low) with methylphenidate to 2·3 (0·66-3·94; very low) with amphetamines for SBP; from 1·60 (0·29-2·91; very low) with methylphenidate to 3·07 (0·69-5·45; very low) with lisdexamfetamine for DBP; and from 4·37 (3·16-5·59; very low) with methylphenidate to 5·8 (2·3-9·3; very low) with viloxazine for pulse. Amphetamines, lisdexamfetamine, or methylphenidate were not associated with larger increments in haemodynamic values compared with atomoxetine or viloxazine in either children and adolescents or adults. Guanfacine was associated with decrements in haemodynamic values in children and adolescents (mean decrease against placebo of -2·83 [95% CI -3·8 to -1·85; low CINeMA confidence] in SBP, -2·08 [-3 to -1·17; low] in DBP, and -4·06 [-5·45 -2·68; moderate] in pulse) and adults (mean decrease against placebo of -10·1 [-13·76 to -6·44; very low] in SBP, -7·73 [-11·88 to -3·58; very low] in DBP, and -6·83 [-10·85 to -2·81; very low] in pulse). Only four RCTs informed on effects in the medium term and none on the long term. INTERPRETATION/CONCLUSIONS:Practitioners should monitor blood pressure and pulse in patients with ADHD treated with any pharmacological intervention, and not stimulants only. Given the short duration of available randomised controlled trials, new research providing insights on the causal effects of ADHD medications on cardiovascular parameters in the longer term should be funded. FUNDING/BACKGROUND:National Institute for Health and Care Research.