Faculty Bibliography

BACKGROUND:The comparative benefits and harms of available interventions for ADHD in adults remain unclear. We aimed to address these important knowledge gaps. METHODS:In this systematic review and component network meta-analysis (NMA), we searched multiple databases for published and unpublished randomised controlled trials (RCTs) investigating pharmacological and non-pharmacological interventions for ADHD in adults from database inception to Sept 6, 2023. We included aggregate data from RCTs comparing interventions against controls or any other eligible active intervention for the treatment of symptoms in adults (ages ≥18 years) with a formal diagnosis of ADHD. Pharmacological therapies were included only if their maximum planned doses were considered eligible according to international guidelines. We included RCTs of at least 1-week duration for medications, of at least four sessions for psychological therapies, and of any length deemed appropriate for neurostimulation. For RCTs of medications, cognitive training, or neurostimulation alone, we included only double-blind RCTs. At least two authors independently screened the identified records and extracted data from eligible RCTs. Our primary outcomes were efficacy (change in ADHD core symptom severity on self-rated and clinician-rated scales at timepoints closest to 12 weeks) and acceptability (all-cause discontinuation). We estimated standardised mean differences (SMDs) and odds ratios (ORs) using random effects pairwise and component NMA, dismantling interventions into specific therapeutic components. This study was registered with PROSPERO (CRD42021265576). People with relevant lived experience were involved in the conduct of the research and writing process. FINDINGS/RESULTS:Of 32 416 records, 113 unique RCTs encompassing 14 887 participants were eligible for analysis (6787 [45·6%] females, 7638 [51·3%] males, 462 [3·1%] sex not reported). The RCTs encompassed pharmacological therapies (63 [55·8%] of 113 RCTs; 6875 participants), psychological therapies (28 [24·8%] of 113 RCTs; 1116 participants), neurostimulatory therapy and neurofeedback (ten [8·8%] of 113 RCTs; 194 participants), and control conditions (97 [85·8%] of 113 RCTs; 5770 participants). For reduction of ADHD core symptoms at 12 weeks on both self-reported and clinician-reported rating scales, atomoxetine (self-reported scale SMD -0·38, 95% CI -0·56 to -0·21; clinician-reported scale -0·51, -0·64 to -0·37) and stimulants (0·39, -0·52 to -0·26; -0·61, -0·71 to -0·51) had higher efficacy than placebo (Confidence in Network Meta-Analysis [CINeMA] ranging between very low and moderate). Cognitive behavioural therapy (-0·76, -1·26 to -0·26), cognitive remediation (-1·35, -2·42 to -0·27), mindfulness (-0·79, -1·29 to -0·29), psychoeducation (-0·77, -1·35 to -0·18), and transcranial direct current stimulation (-0·78; -1·13 to -0·43) were better than placebo only on clinician-reported measures. Regarding acceptability, all therapeutic components were similar to placebo other than atomoxetine (OR 1·43, 95% CI 1·14 to 1·80; CINeMA moderate) and guanfacine (3·70, 1·22 to 11·19; high), which had lower acceptability compared with placebo. Baseline severity of self-reported ADHD core symptoms, year of publication, percentage of male individuals, and percentage of individuals with ADHD and another mental health condition did not explain the heterogeneity observed in unadjusted non-component models of self-reported ADHD core symptoms. Treatment length had little effect on heterogeneity. INTERPRETATION/CONCLUSIONS:Stimulants and atomoxetine were the only interventions with evidence of beneficial effects in terms of reducing ADHD core symptoms in the short term, supported by both self-reported and clinician-reported ratings. However, atomoxetine was less acceptable than placebo. Medications for ADHD were not efficacious on additional relevant outcomes, such as quality of life, and evidence in the longer term is underinvestigated. The effects of non-pharmacological strategies were inconsistent across different raters. Our network meta-analysis represents the most comprehensive synthesis of available evidence to inform future guidelines in the field. FUNDING/BACKGROUND:UK National Institute for Health and Care Research.

For many years, the hilus of the dentate gyrus (DG) was a mystery because anatomical data suggested a bewildering array of cells without clear organization. Moreover, some of the anatomical information led to more questions than answers. For example, it had been identified that one of the major cell types in the hilus, the mossy cell, innervates granule cells (GCs). However, mossy cells also targeted local GABAergic neurons. Furthermore, it was not yet clear if mossy cells were glutamatergic or GABAergic. This led to many debates about the role of mossy cells. However, it was clear that hilar neurons, including mossy cells, were likely to have very important functions because they provided strong input to GCs. Hilar neurons also attracted attention in epilepsy because pathological studies showed that hilar neurons were often lost, but GCs remained. Vulnerability of hilar neurons also occurred after traumatic brain injury and ischemia. These observations fueled an interest to understand hilar neurons and protect them, an interest that continues to this day. This article provides a historical and personal perspective into the ways that I sought to contribute to resolving some of the debates and moving the field forward. Despite several technical challenges the outcomes of the studies have been worth the effort with some surprising findings along the way. Given the growing interest in the hilus, and the advent of multiple techniques to selectively manipulate hilar neurons, there is a great opportunity for future research.

Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary DG cell type, granule cells (GCs). Numerous MC synapses are on GC proximal dendrites in the inner molecular layer (IML). However, field recordings of the GC excitatory postsynaptic potential (fEPSPs) have not been used to study this pathway selectively. Here we describe methods to selectively activate MC axons in the IML using mice with Cre recombinase expressed in MCs. Slices were made after injecting adeno-associated virus (AAV) encoding channelrhodopsin (ChR2) in the DG. In these slices, we show that fEPSPs could be recorded reliably in the IML in response to optogenetic stimulation of MC axons. Furthermore, fEPSPs were widespread across the septotemporal axis. However, fEPSPs were relatively weak because they were small in amplitude and did not elicit a significant population spike in GCs. They also showed little paired pulse facilitation. We confirmed the extracellular findings with patch clamp recordings of GCs despite different recording chambers and other differences in methods. Together the results provide a simple method for studying MC activation of GCs and add to the evidence that this input is normally weak but widespread across the GC population.

The coexistence of mental and physical health illnesses could be accounted for by an underlying general disease factor (termed d-factor), reflecting theoretical underpinnings based on possible genetic and pathophysiological overlapping mechanisms. This study evaluated whether the d-factor underlies mental and physical health illnesses in adolescents. A series of confirmatory factor analyses were conducted using data from 1120 adolescents. The proposed common underlying factor, we believe is the d-factor, was consistently present across different modeling approaches, including unidimensional, correlated-factor, and bifactor models. The best model fit was achieved with the bifactor model represented by mental, neurological, and psychical conditions tested. The first compelling evidence was provided supporting the existence of the transdiagnostic d-factor in youth, opening the door to innovative research of comorbid mental and physical health conditions.

The use of prostaglandin infusion to maintain patency of the ductus arteriosus in patients with critical coarctation of the aorta (CoA) to support systemic circulation is the standard of care. However, pulmonary overcirculation resulting from a patent ductus arteriosus in patients with critical CoA is not well described in the literature. We report two cases of critical CoA that required invasive measures to control pulmonary blood flow before surgical repair of the CoA. Both patients had signs of decreased oxygen delivery, hyperlactatemia, and systemic to pulmonary flow via the ductus arteriosus. One patient required surgical pulmonary artery banding and the second patient underwent pulmonary flow restrictor device placement for the control of pulmonary blood flow. A rapid improvement in oxygen delivery and normalization of lactate levels were observed after control of pulmonary overcirculation. Both patients underwent successful surgical repair of the coarctation A and were discharged home.

Weighing risks and benefits of the use of psychotropic medications during pregnancy remains a challenge worldwide. We systematically assessed the strength of associations between psychotropic medication use in pregnant people with mental disorders and various adverse health outcomes in both pregnant people and foetuses. Systematic reviews with meta-analyses of observational studies investigating the association between exposure to psychotropic medication in pregnancy and any adverse health outcomes were included. Credibility was graded into convincing, highly suggestive, suggestive, weak or not significant. Quality of the meta-analyses and of individual studies were assessed with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) the Newcastle-Ottawa Scale (NOS), respectively. We considered 21 meta-analyses encompassing 17,290,755 participants (AMSTAR 2 high = 1, low = 12, or critically low = 8). Evidence was suggestive for: (1) preterm birth in pregnant people with either any mental disorder (equivalent odds ratio 1.62 (95% confidence interval 1.24-2.12) or depression (1.65 [1.34-2.02]) receiving antidepressants during any trimester of pregnancy; (2) small for gestational age for pregnant people with depression receiving a SSRI during any trimester of pregnancy (1.50 [1.19-1.90]); and (3) major congenital malformation (1.24 [1.09-1.40]) or cardiac malformations (1.28 [1.11-1.47]) in babies for pregnant people with depression or anxiety receiving paroxetine during first trimester of pregnancy. Additional associations were supported by weak evidence, or were not statistically significant. This umbrella review found no convincing or highly suggestive level of evidence of adverse health outcomes associated with psychotropic medication use in pregnant people with mental disorders.

Palliative care improves the quality of life for seriously ill patients, but misconceptions and knowledge gaps hinder its implementation in home healthcare (HHC). This study developed and pilot-tested HHC-specific questionnaires to measure palliative care knowledge, attitudes, and confidence (PC-KAC) among clinicians, patients, and caregivers. Using literature reviews, expert input, and cognitive interviews, the questionnaires were refined to ensure clarity, practical relevance, and content validity. Pilot testing revealed widespread confusion about palliative care, with patients and caregivers often conflating it with hospice care and holding misconceptions about opioid use for pain and symptom management. While clinicians demonstrated adequate knowledge, gaps in pain management and confidence in handling emergencies were evident. These findings highlight the need for targeted education and training to integrate palliative care effectively into HHC, improving patient outcomes and supporting interdisciplinary collaboration.

Gestational diabetes mellitus (GDM) affects around 10% of pregnancies in the United States and has been linked to neurodevelopmental sequelae in children. However, there is a paucity of studies investigating early-life neural markers in GDM-exposed infants. This study examined the association of GDM with relative EEG power among healthy term-age neonates collected during natural sleep. Participants included a diverse cohort of 101 mothers (45% multiracial, 25% Black, and 69% Hispanic or Latina) and their infants (gestational age at birth M_age = 39.0 ± 0.95; 46.5% female). We did not observe the main effect of GDM on infant relative EEG power. Our post hoc analyses revealed a significant interaction effect between GDM and infant birth weight on relative EEG power in active sleep. Among GDM-exposed neonates, increased birth weight was associated with increased relative theta EEG power and decreased relative beta and gamma EEG power across multiple electrode regions. Among non-GDM-exposed infants, increased birth weight was associated with decreased relative theta EEG power and increased relative beta and gamma EEG power across multiple electrode regions. Our findings suggest that alterations in fetal growth may serve as either an indirect marker or pathway through which GDM influences the developing fetal brain.

BACKGROUND:Sleep problems are reported for up to 80% of autistic individuals. We examined whether parsimonious sets of items derived from the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) and the Brief Infant Sleep Questionnaire (BISQ) are superior to the standard M-CHAT-R in predicting subsequent autism spectrum disorder (ASD) diagnoses. METHODS:Participants from 11 Environmental influences on Child Health Outcomes (ECHO) cohorts were included. We performed logistic LASSO regression models with 10-fold cross-validation to identify whether a combination of items derived from the M-CHAT-R and BISQ are superior to the standard M-CHAT-R in predicting ASD diagnoses. RESULTS:The final sample comprised 1552 children. The standard M-CHAT-R had a sensitivity of 44% (95% CI: 34, 55), specificity of 92% (95% CI: 91, 94), and AUROC of 0.726 (95% CI: 0.663, 0.790). A higher proportion of children with ASD had difficulty falling asleep or resisted bedtime during infancy/toddlerhood. However, LASSO models revealed parental reports of sleep problems did not improve the accuracy of the M-CHAT-R in predicting ASD diagnosis. CONCLUSION/CONCLUSIONS:While children with ASD had higher rates of sleep problems during infancy/toddlerhood, there was no improvement in ASD developmental screening through the incorporation of parent-report sleep metrics. IMPACT/CONCLUSIONS:Parental-reported sleep problems are common in autism spectrum disorder (ASD). We investigated whether the inclusion of parental-reports of infant/toddler sleep patterns enhanced the effectiveness of developmental screening for autism. We reported higher rates of difficulty falling asleep and resisting bedtime during infancy and toddlerhood among children later diagnosed with ASD; however, we did not find an improvement in ASD developmental screening through the incorporation of parent-report sleep metrics. In our sample, the standard M-CHAT-R had a sensitivity of 39% among children of mothers with government insurance compared with a sensitivity of 53% among children of mothers with employer-based insurance.