Faculty Bibliography

This update and revision of the international guideline for urticaria was developed in accordance with the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is an initiative of the Global Allergy and Asthma Excellence Network (GA²LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), with the participation of 210 delegates from 107 national and international societies, from 59 countries. The consensus conference was held on December 6th, 2024. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, defined by a rapid appearance of wheals, angioedema, or both. The lifetime prevalence of acute urticaria is estimated to be approximately 20%. Chronic urticaria, categorized as either chronic spontaneous urticaria or chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school, however, novel therapies are available. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Individuals with attention-deficit/hyperactivity disorder, their families and clinicians may report worsening symptoms despite compliant use of medication, suggesting potential tolerance, but evidence remains conflicting. Some studies have also suggested tachyphylaxis, or acute tolerance, though research is limited. We conducted the first systematic review of empirical studies focussing on tolerance/tachyphylaxis to attention-deficit/hyperactivity disorder medication to clarify their potential clinical relevance. METHODS:As registered on PROSPERO (CRD42024594759), we searched PubMed, OVID (including PsychInfo and MEDLINE) and Web of Knowledge up to 1 September, 2024, and assessed the risk of bias using National Institutes of Health quality assessment tools. RESULTS:The identified 17 studies were either interventional or observational, and varied greatly in design and duration. Four investigated tachyphylaxis, nine tolerance to the subjective and behavioural effects, and four tolerance to cardiovascular effects. We found preliminary evidence of tachyphylaxis to the affective or behavioural effects of stimulants, as well as tolerance to the subjective effects of d-amphetamine, such as drug liking and excitation, in neurotypical volunteers in the short term. Conversely, there was little or no evidence for tolerance to the therapeutic or cardiovascular effects of attention-deficit/hyperactivity disorder medication in clinical settings in the longer term. Quality was rated as low in most studies because of small sample sizes and methodological limitations. CONCLUSIONS:Overall, these results do not support the hypothesis that tolerance commonly develops to the therapeutic effects of attention-deficit/hyperactivity disorder medication, although robustly designed longitudinal studies are needed to provide more conclusive evidence. Clinicians may consider other potential explanations for reduced therapeutic effects over time, including natural fluctuations of symptoms, limited compliance, life events and co-occurrent mental health conditions.

Socioeconomic disadvantage has been established as a key risk factor for adverse child behavioral outcomes. Understanding how individual components of socioeconomic status (SES) interact with each other can elucidate protective factors and inform interventions and policies to promote positive developmental outcomes. This study examined the interactive effects of prenatal household income and neighborhood deprivation on child externalizing and internalizing problems (N = 793; M

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.

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.

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.

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 .

This is the first bottom-up review of the lived experience of persons who attempt suicide. The study has been co-designed, co-conducted and co-written by experts by experience and academics, focusing on first-person narratives within and outside the medical field. The lived world of individuals who attempt suicide is characterized by experiences related to the attempt itself ("contemplating suicide as a deliberate death", "contemplating suicide as an escape route", "looking for online answers about suicide", "planning suicide", "finding rest between the suicidal decision and the final act", "changing one's mind during the suicide attempt", "acting on suicidal impulses"); experiences related to the self and time ("feeling unworthy", "feeling detached from oneself or the world and lacking a sense of agency", "splitting the self between the decision to live or die", "perceiving an abortive and doomed future"); and experience of emotions and the body ("feeling overwhelmed by hopelessness and despair", "feeling empty and drained of energy", "feeling alone"). The lived experience of individuals who attempt suicide is also described in terms of the social and cultural context, including the experience of others ("feeling that no one cares", "feeling like a burden to others", "facing others' difficulty in understanding"); cultural, gender and age differences ("experiencing geographical, cultural and religious taboos about suicide", "feeling inadequate in relation to gender stereotypes", "feeling abandoned in old age"); and the perception of stigma ("facing social stigma", "experiencing a stigmatized self", "silencing suicidal behaviors"). The lived experience of persons after an attempted suicide is characterized as a complex process of self-acceptance and rediscovery ("living with suicidal thoughts", "navigating the challenges of recovery", "gaining new perspectives during recovery", "restoring interpersonal relationships to recover"). Finally, the lived experience of individuals who attempt suicide is described with respect to their access to general health care ("seeking help before the suicide attempt", "feeling abandoned after a suicide attempt") and mental health care ("experiencing shame as a barrier to care", "fearing mental disorder label", "feeling accepted and listened to", "facing economic difficulties in accessing support", "coping with distress during hospitalization"). The experiences described in this paper hold educational and social value, informing medical and psychological practices and research, public health approaches, and promotion of social change. This research overcomes embarrassment, fear and stigma, and helps us to understand the fragile nature of our emotions and feelings, our immersion in the social world, and our sense of meaning in life.

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.

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.