Faculty Bibliography

BACKGROUND:People with mental disorders have an increased risk of diabetes, yet conflicting evidence exists regarding the quality of diabetes care they receive. To address this evidence gap, we conducted a systematic review and meta-analysis to assess and compare diabetes quality of care in people with diabetes with mental disorders versus people with diabetes without mental disorders. METHODS:test, blood pressure measured, foot surveillance, serum creatinine test, serum cholesterol test, BMI recorded, smoking status recorded, retinal monitoring). Secondary outcomes were study-specific diabetes quality of care individual indicators matched to the nine NICE diabetes monitoring indicators and specific diabetes interventions and anti-diabetes medications. We analysed primary and secondary outcomes according to any mental disorder and to specific diagnostic subgroups. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS). FINDINGS/RESULTS:measurement (24 studies, 0·81 [0·68-0·97], p=0·024), retinal screening (21 studies, 0·77 [0·63-0·95], p=0·013), lipid and cholesterol measurement (20 studies, 0·83 [0·69-0·99], p=0·043), foot examination (11 studies, 0·85 [0·76-0·95], p=0·0044), and renal investigation (16 studies, 0·78 [0·63-0·96], p=0·022). A significant positive association was found between any mental disorder and recorded smoking status (two studies, 1·09 [1·02-1·17]; p=0·0076). Any mental disorder was significantly associated with higher odds of receiving insulin (ten studies, 1·52 [95% CI 1·16-1·99]; p=0·0022), but negatively associated with treatment with a GLP-1 receptor agonist (two studies, 0·26 [0·13-0·49]; p<0·0001). There was no evidence of publication bias. INTERPRETATION/CONCLUSIONS:Mental disorders are negatively associated with receiving adequate diabetes monitoring and GLP-1 agonist therapy. Addressing these disparities has the potential to address the increased mortality associated with mental disorders. FUNDING/BACKGROUND:None.

BackgroundRates of psychiatric disorders and related hospitalizations among youth in the United States have risen substantially over recent decades. Despite evidence supporting outpatient care, fewer than half of youth receive treatment. When outpatient management is insufficient, inpatient psychiatric hospitalization is required, though it is costly, disruptive, and limited in availability. Prior research on predictors of inpatient length of stay has been dated and heterogenous, highlighting the need to identify current clinical and non-clinical factors associated with prolonged stays among youth populations.MethodThis IRB-approved retrospective study reviewed the medical records of 1,101 child and adolescent patients admitted to an inpatient psychiatric unit between June 1, 2018, and November 30, 2021. Baseline sociodemographic and clinical data were collected, and LOS was categorized into three groups: below-average (0-6 days), average (7-14 days), and above-average (15+ days). Comparative statistics were performed, and linear regression was used to identify independent predictors of LOS.ResultsThe average LOS was 10.5 days. Significant predictors of prolonged LOS included public insurance, admission for psychosis or suicide attempt, involvement of child protective services, number of prior hospitalizations, and number of medications prior to admission.ConclusionProlonged LOS in psychiatrically hospitalized youth is associated with specific clinical and non-clinical factors. Identifying these predictors at admission can guide treatment planning and set realistic expectations for families. Further research is required to validate these findings and explore the impact of LOS on treatment outcomes.

Despite decades of neuroimaging research, how white matter develops along the length of major tracts in humans remains unknown. Here, we identify fundamental patterns of white matter maturation by examining developmental variation along major, long-range cortico-cortical tracts in youth ages 5-23 years using diffusion MRI from three large-scale, cross-sectional datasets (total N = 2716). Across datasets, we delineate two replicable axes of human white matter development. First, we find a deep-to-superficial axis, in which superficial tract regions near the cortical surface exhibit greater age-related change than deep tract regions. Second, we demonstrate that the development of superficial tract regions aligns with the cortical hierarchy defined by the sensorimotor-association axis, with tract ends adjacent to sensorimotor cortices maturing earlier than those adjacent to association cortices. These results reveal developmental variation along tracts that conventional tract-average analyses have previously obscured, challenging the implicit assumption that white matter tracts mature uniformly along their length. Such developmental variation along tracts may have functional implications, including mitigating ephaptic coupling in densely packed deep tract regions and tuning neural synchrony through hierarchical development in superficial tract regions - ultimately refining neural transmission in youth.

OBJECTIVE:To assess associations between exposure to intrauterine SARS-CoV-2 and subsequent child neurodevelopment in a large, diverse cohort with confirmation of maternal SARS-CoV-2 status. STUDY DESIGN/METHODS:edition (ASQ-3) and at 18 months with the ASQ Social-Emotional (ASQ-SE) and the Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R). We compared exposed and unexposed infants' ASQ-3 total and subdomain scores, ASQ-SE and M-CHAT-R scores, and proportions meeting published referral thresholds, using multivariable linear and logistic regression. RESULTS:Among 1179 participants enrolled, 1008 (85.5%) had exposure, with 806 (80.0%) exposed during Omicron predominance. Of those with known timing, 349 (41.4%) and 295 (35.0%) were exposed in the second and third trimesters of pregnancy respectively. Exposure was not associated with differences in ASQ-3 (adjusted difference: -0.61, 95% CI: -10.03, 8.81) or ASQ-3 subdomains at 12 months, ASQ-SE at 18 months (adjusted difference: 0.19, 95% CI: -4.02, 4.41), or M-CHAT-R scores. Findings were similar for proportions meeting referral thresholds, and when stratified by variant or by trimester. CONCLUSIONS:In this multicenter cohort largely exposed since Omicron and in second or third trimester, intrauterine SARS-CoV-2 exposure was not associated with neurodevelopmental screening outcomes through 18 months of age. Further assessments of the impact of intrauterine SARS-CoV-2 on neurodevelopment beyond 18 months of age are needed.

External trigeminal nerve stimulation (TNS) received US Food and Drug Administration clearance in 2019 as the first device-based, non-pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), based on a small pilot sham-controlled randomized controlled trial (RCT) that reported symptom improvement in 62 children with ADHD. Here we conducted a confirmatory multicenter, double-blind, randomized, sham-controlled, parallel-group, phase 2b RCT to investigate short-term and long-term efficacy (6 months) of real versus sham TNS in 150 children and adolescents with ADHD. Participants were randomized to receive real TNS (n = 75, mean age (s.d.) = 12.6 (2.8) years) or sham TNS (n = 75, mean age (s.d.) = 12.6 (2.8) years) nightly for approximately 9 hours for 4 weeks. Bilateral stimulation targeted V1 trigeminal branches using battery-powered electrodes applied to the forehead. Sham TNS delivered 30 seconds of stimulation per hour at lower frequency and pulse width. Intention-to-treat analysis showed no significant differential treatment effects on ADHD symptoms (primary outcome) (estimated adjusted mean difference = 0.83; 95% confidence interval: -2.47 to 4.13; P = 0.622; Cohen's d = 0.09). No serious adverse events were reported, and side effects did not differ between groups. In conclusion, TNS is a safe intervention but does not demonstrate clinical efficacy for pediatric ADHD. Trial registration: ISRCTN82129325 .

BACKGROUND:Negative reactivity (NR) and behavioral inhibition (BI), temperamental traits characterized by novelty-evoked distress and avoidance respectively, represent risk markers for anxiety. However, not all infants with NR and BI develop anxiety. Pathways from infant temperament to anxiety remain underspecified. This study tests the hypothesis that heightened neural sensitivity to unexpected sensory stimuli in infancy moderates risk for anxiety. METHODS:Data from the Temperament Over Time Study (N=291) were utilized. Infants completed laboratory-based assessments of NR at 4 months (M) and BI at 2-3 years. BI was also assessed using parent-report. At 9 and 36M, electroencephalography was collected during a passive three-stimulus auditory oddball task, and the mismatch response (MMR) and novelty P3 were quantified. Adolescent anxiety was measured using parent- and self-reports, and clinical interviews at 13 and 15 years. Structural equational modeling analyses were applied to examine whether infants' MMR or novelty P3 at 9 and 36M modulate relations between NR, BI, and adolescent anxiety. RESULTS:The MMR at 9M moderated the relation between NR and BI, and the MMR at 36M moderated the relation between BI and 13-year anxiety. In both cases, a more negative MMR was associated with elevated risk. This association was not present for attention problems or externalizing outcomes. Additional exploratory analyses showed that the novelty P3 mediated pathways from NR to social anxiety. CONCLUSIONS:Individual differences in the infant's neural response to unexpected stimuli relate to temperamental risk for anxiety.

Osteoarthritis, especially knee osteoarthritis, is a leading cause of disability and reduced quality of life. The etiology of pain in osteoarthritis is multifactorial, and one promising potential treatment approach involves targeting chemokine systems. The present study was a phase 2, multisite, multiperiod randomized crossover trial of CNTX-6970, a small molecule and selective oral cytokine chemokine receptor type 2 (CCR2) and CCR5 antagonist, in patients with painful knee osteoarthritis (OA). It represents the first trial performed within the National Institutes of Health's Early Phase Pain Investigation Clinical Network. The primary objectives were to evaluate the safety and efficacy of CNTX-6970, relative to placebo, for the treatment of moderate to severe pain related to knee OA. A total of 55 participants were randomized in this multiperiod crossover trial. Linear mixed effects models revealed no significant pain-related benefits of active medication; indeed, trial participants reported slightly higher knee pain intensity when taking the novel chemokine antagonist CNTX-6970 than when taking placebo. In addition, biomarker analysis revealed notably higher level of serum monocyte chemoattractant protein 1 levels when patients were on CNTX-6970 compared to placebo. Overall, although CNTX-6970 was safe and relatively well-tolerated, pharmacologic blockade of specific chemokine receptors with this compound was not effective in reducing moderate-to-severe knee osteoarthritis pain.

IMPORTANCE/UNASSIGNED:Millions of children worldwide are experiencing prolonged symptoms after SARS-CoV-2 infection, yet social risk factors for developing long COVID are largely unknown. As child health is influenced by the environment in which they live and interact, adverse social determinants of health (SDOH) may contribute to the development of pediatric long COVID. OBJECTIVE/UNASSIGNED:To identify whether adverse SDOH are associated with increased odds of long COVID in school-aged children and adolescents in the US. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional analysis of a multicenter, longitudinal, meta-cohort study encompassed 52 sites (health care and community settings) across the US. School-aged children (6-11 years; n = 903) and adolescents (12-17 years; n = 3681) with SARS-CoV-2 infection history were included. Those with an unknown date of first infection, history of multisystem inflammatory syndrome in children, or symptom surveys with less than 50% of questions completed were excluded. Participants were recruited via health care systems, long COVID clinics, fliers, websites, social media campaigns, radio, health fairs, community-based organizations, community health workers, and existing research cohorts from March 2022 to August 2024, and surveys were completed by caregivers between March 2022 and August 2024. EXPOSURE/UNASSIGNED:Twenty-four individual social determinant of health factors were grouped into 5 Healthy People 2030 domains: economic stability, social and community context, caregiver education access and quality, neighborhood and built environment, and health care access and quality. Latent classes were created within each domain and used in regression models. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Presence of long COVID using caregiver-reported, symptom-based, age-specific research indices. RESULTS/UNASSIGNED:The mean (SD) age among 4584 individuals included in this study was 14 (3) years, and 2330 (51%) of participants were male. The number of latent classes varied by domain; the reference group was the class with the least adversity. In unadjusted analyses, most classes in each domain were associated with higher odds of long COVID. After adjusting for many factors, including age group, sex, timing of infection, referral source, and other social determinant of health domains, economic instability characterized by difficulty covering expenses, poverty, receipt of government assistance, and food insecurity were associated with an increased risk of having long COVID (class 2 adjusted odds ratio [aOR], 1.57; 95% CI, 1.18-2.09; class 4 aOR, 2.39; 95% CI, 1.73-3.30); economic instability without food insecurity (class 3) was not (aOR, 0.93; 95% CI, 0.70-1.23). Poorer social and community context (eg, high levels of discrimination and low social support) was also associated with long COVID (aOR, 2.17; 95% CI, 1.77-2.66). Sensitivity analyses stratified by age group and adjusted for race and ethnicity did not alter or attenuate these results. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this study, economic instability that included food insecurity and poor social and community context were associated with greater odds of pediatric long COVID. Those with food security, despite experiencing other economic challenges, did not have greater odds of long COVID. Further study is needed to determine if addressing SDOH factors can decrease the rate of pediatric long COVID.

Pyramidal cells (PCs) of hippocampal area CA2 exhibit increased excitability in temporal lobe epilepsy (TLE) and in mouse models of TLE. In epileptic mice, selective inhibition of CA2 PCs reduces chronic seizures. Here we asked if activating CA2 PCs increases seizures. Mice expressing Cre recombinase in CA2 PCs (Amigo2-Cre mice) were injected with the convulsant pilocarpine to induce a period of severe seizures (status epilepticus, SE), which leads to chronic seizures after 3-4 weeks (epilepsy). Epileptic mice were injected with a Cre-dependent adeno-associated virus (AAV) to express an excitatory designer receptor exclusively activated by designer drug (eDREADD; hM3Dq) in dorsal CA2 bilaterally and implanted with subdural EEG electrodes. After recovery, mice were recorded continuously using video and EEG for 6 weeks, 3 weeks with drinking water containing the eDREADD activator clozapine-N-oxide (CNO) and 3 weeks without CNO. CA2 activation with CNO caused a significant increase in seizure frequency and duration. Seizures occurred in clusters (many seizures per day over several consecutive days) and mice given water with CNO had a greater maximum number of seizures per day during a cluster compared to water without CNO. CNO had no significant effect in control mice. In naïve Amigo2-Cre mice expressing hM3Dq, pre-treatment with CNO before pilocarpine administration shortened the latency to SE and increased EEG power at the start of SE. Taken together with prior findings, the results suggest that CA2 is a control point for regulating seizures in the pilocarpine mouse model of TLE.