Faculty Bibliography

Translational neuroscience for anxiety has had limited success despite great progress in understanding the neurobiology of Pavlovian fear conditioning and extinction. This chapter explores the idea that conditioning paradigms have had a modest impact on translation because studies in animals and humans are misaligned in important ways. For instance, animal conditioning studies typically use imminent threats to assess short-duration fear states with single behavioral measures (e.g., freezing), whereas human studies typically assess weaker or more prolonged anxiety states with physiological (e.g., skin conductance) and self-report measures. A path forward may be more animal research on conditioned anxiety phenomena measuring dynamic behavioral and physiological responses in more complex environments. Exploring transitions between defensive brain states during extinction, looming threats, and post-threat recovery may be particularly informative. If care is taken to align paradigms, threat levels, and measures, this strategy may reveal stable patterns of non-conscious defense in animals and humans that correlate better with conscious anxiety. This shift in focus is also warranted because anxiety is a bigger problem than fear, even in disorders defined by dysfunctional fear or panic reactions.

BACKGROUND/UNASSIGNED:Topical therapy has been shown to induce an immune response in patients with hepatocellular carcinoma (HCC). In this study, a prospective parallel group control experiment was conducted to compare the differences between radiofrequency ablation and microwave ablation in inducing the immune regulation of NK cells. METHODS/UNASSIGNED:Sixty patients with clinically and pathologically confirmed hepatitis B-associated hepatocellular carcinoma (HCC) were selected for thermal ablation. Patients were randomly assigned into the MWA group (n = 30) and the RFA group (n = 30). Patient's peripheral blood was isolated on days D0, D7, and month M1. NK cell subsets, receptors, and killing function were detected by flow cytometry and LDH. Student t test and rank sum test were used to compare the statistical differences between the RFA (radio frequency) and MWA (microwave) groups. The Kaplan-Meier curve and log-rank test were used to calculate the difference between the two survival curves. RESULTS/UNASSIGNED:Comparison of the frequency of CD3-CD56+ and CD3-CD56+CD16+ in NK cells between the RFA and WMA groups showed that there was no difference in the D0, D7, M1, D7-D0, M1-D0, and M1-D7 groups. The changes of the inhibitory NK cell receptor CD159A were significantly different at D7 (P<0.05). CD107a were compared between the RFA and WMA groups, indicating that CD107a changes induced by NK cells were significantly different at D7-D0 (P<0.05). Comparison of NK cell lysis activity of target K562 cells between the RFA and WMA groups showed that there was no difference at D0, D7, D7-D0. There was no difference in recurrence-free survival (RFS) between the RFA and WMA groups (P=0.11). CONCLUSIONS/UNASSIGNED:The difference between MWA and RFA-induced NK cell changes was mainly manifested in the inhibitory receptors CD159a and CD107a 1 week after surgery, with microwave-induced changes being more severe. Comparison of the NK cell lysis activity of the target K562 cells between the RFA and WMA groups showed that there was no difference in D0, D7, D7- D0. Survival analysis showed that these differences did not affect the recurrence-free survival (RFS) in the two groups.

Developmental exposure to ethanol is a leading cause of cognitive, emotional and behavioral problems, with fetal alcohol spectrum disorder (FASD) affecting more than 1:100 children. Recently, comorbid sleep deficits have been highlighted in these disorders, with sleep repair a potential therapeutic target. Animal models of FASD have shown non-REM (NREM) sleep fragmentation and slow-wave oscillation impairments that predict cognitive performance. Here we use a mouse model of perinatal ethanol exposure to explore whether reduced sleep pressure may contribute to impaired NREM sleep, and compare the function of a brain network reported to be impacted by insomnia-the Salience network-in developmental ethanol-exposed mice with sleep-deprived, saline controls. Mice were exposed to ethanol or saline on postnatal day 7 (P7) and allowed to mature to adulthood for testing. At P90, telemetered cortical recordings were made for assessment of NREM sleep in home cage before and after 4 h of sleep deprivation to assess basal NREM sleep and homeostatic NREM sleep response. To assess Salience network functional connectivity, mice were exposed to the 4 h sleep deprivation period or left alone, then immediately sacrificed for immunohistochemical analysis of c-Fos expression. The results show that developmental ethanol severely impairs both normal rebound NREM sleep and sleep deprivation induced increases in slow-wave activity, consistent with reduced sleep pressure. Furthermore, the Salience network connectome in rested, ethanol-exposed mice was most similar to that of sleep-deprived, saline control mice, suggesting a sleep deprivation-like state of Salience network function after developmental ethanol even without sleep deprivation.

INTRODUCTION:There is a striking knowledge gap on ADHD in older adults, and the diagnosis as well as treatment for ADHD in this age group. AREAS COVERED:The authors first review the literature on the prevalence, functional impairment, and health comorbidities of ADHD across the lifespan. Next, they address the diagnostic criteria for ADHD in adults according to the DSM/ICD, available screening/diagnostic tools, differential diagnosis, and the validity of diagnostic criteria for ADHD in older adults. Finally, the authors focus on empirical evidence on the prevalence rates, medication response, and safety of pharmacological treatment of ADHD in older adults, and national and international clinical guidelines on the treatment of ADHD in this age group. EXPERT OPINION:It is expected that future editions of the DSM and ICD will provide specifiers to the standard ADHD criteria, to better inform the diagnosis of ADHD in older adults. It is also expected that the increasing number of epidemiological studies will provide rigorous estimates on the prevalence, incidence, and burden of ADHD in older adults. One may expect an increasing number of RCTs assessing the efficacy/effectiveness and tolerability/safety of pharmacological as well as non-pharmacological interventions which will inform future guidelines on ADHD in older adults.

BACKGROUND:In the short term, parental presence while a human infant is in pain buffers the immediate pain responses, although emerging evidence suggests repeated social buffering of pain may have untoward long-term effects. METHODS/FINDING/UNASSIGNED:To explore the short- and long-term impacts of social buffering of pain, we first measured the infant rat pup's [postnatal day (PN) 8, or 12] response to mild tail shock with the mother present compared to shock alone or no shock. Shock with the mother reduced pain-related behavioral activation and USVs of pups at both ages and reduced Fos expression in the periaqueductal gray, hypothalamic paraventricular nucleus, and the amygdala at PN12 only. At PN12, shock with the mother compared to shock alone differentially regulated expression of several hundred genes related to G-protein-coupled receptors (GPCRs) and neural development, whereas PN8 pups showed a less robust and less coherent expression pattern. In a second set of experiments, pups were exposed to daily repeated Shock-mother pairings (or controls) at PN5-9 or PN10-14 (during and after pain sensitive period, respectively) and long-term outcome assessed in adults. Shock+mother pairing at PN5-9 reduced adult carrageenan-induced thermal hyperalgesia and reduced Fos expression, but PN10-14 pairings had minimal impact. The effect of infant treatment on adult affective behavior showed a complex treatment by age dependent effect. Adult social behavior was decreased following Shock+mother pairings at both PN5-9 and PN10-14, whereas shock alone had no effect. Adult fear responses to a predator odor were decreased only by PN10-14 treatment and the infant Shock alone and Shock+mother did not differ. CONCLUSIONS/SIGNIFICANCE/CONCLUSIONS:Overall, integrating these results into our understanding of long-term programming by repeated infant pain experiences, the data suggest that pain experienced within a social context impacts infant neurobehavioral responses and initiates an altered developmental trajectory of pain and affect processing that diverges from experiencing pain alone.

Evolving medical technologies have motivated the development of treatment decision rules (TDRs) that incorporate complex, costly data (e.g., imaging). In clinical practice, we aim for TDRs to be valuable by reducing unnecessary testing while still identifying the best possible treatment for a patient. Regardless of how well any TDR performs in the target population, there is an associated degree of uncertainty about its optimality for a specific patient. In this paper, we aim to quantify, via a confidence measure, the uncertainty in a TDR as patient data from sequential procedures accumulate in real-time. We first propose estimating confidence using the distance of a patient's vector of covariates to a treatment decision boundary, with further distances corresponding to higher certainty. We further propose measuring confidence through the conditional probabilities of ultimately (with all possible information available) being assigned a particular treatment, given that the same treatment is assigned with the patient's currently available data or given the treatment recommendation made using only the currently available patient data. As patient data accumulate, the treatment decision is updated and confidence reassessed until a sufficiently high confidence level is achieved. We present results from simulation studies and illustrate the methods using a motivating example from a depression clinical trial. Recommendations for practical use of the measures are proposed.

OBJECTIVE:To describe a sample of minoritized youth who screened positive for suicide risk within medical subspecialty pediatrics, compared to non-minoritized youth and describe the screening outcomes of these youth. METHODS:This retrospective chart review from October 2018 to April 2021 used electronic medical record data from an academic pediatric medical subspecialty clinic that screens universally for suicide risk for all patients ages 9 and up. Chart reviews were conducted for 237 minoritized youth (operationalized as identifying as non-White or Hispanic/Latinx, identifying as a gender minority, and having a preferred language other than English) who screened positive for suicide risk. Descriptive statistics include need for escalation to an emergency room, connection to mental health care, receival of a mental health referral, and attendance at follow-up visits. RESULTS:Minoritized youth were more likely to screen positive and report a history of suicide attempt when compared to non-minoritized peers. Youth identifying as gender expansive had significant elevation in suicide risk. The majority of youth in this sample were already connected to mental health care, with youth preferring a language other than English being the least likely to be connected. CONCLUSIONS:Findings indicate heightened suicide risk for minoritized youth, with gender expansive youth having particularly elevated suicide risk. A need to support youth with a preferred language other than English in getting connected to mental health care was also revealed.

IMPORTANCE/OBJECTIVE:Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. METHODS:RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. DISCUSSION/CONCLUSIONS:RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. CLINICAL TRIALS.GOV IDENTIFIER/BACKGROUND:Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

The e-cigarette (EC) epidemic began in the United States (US) in 2007; since 2014 EC is the most commonly used form of tobacco. However, the mental health implications of vaping are grossly unknown. The aim of this umbrella review is to provide astate-of-the-art summary of existing research concerning vaping and mental health conditions in children. Following the PRISMA Statement 2020 guidelines, a systematic search was conducted across PubMed, Cochrane Library, and Google Scholar up to April 15th, 2022 to locate relevant studies. The Joana Briggs Institute (JBI) methodology for umbrella reviews and quality appraisal tool was utilized. Six studies, pooling a total of 846,510 adolescents aged 21 years or below, were included by collating 85 primary clinical studies. Of these, 58.8% of the primary clinical studies originated in the US, with 4.7% from Canada, South Korea, and the United Kingdom each; 3.5% each from England and Taiwan; 2.4% each from Australia, France, Hawaii, Mexico, and Russia; and 1.2% each from Denmark, Greece, Hong Kong, Iceland, New Zealand, Poland, and Switzerland. Overall, significant associations were found between mental health outcomes, including depression and suicidality, among current EC users and those who had ever used EC. Compared to adolescents who had never used EC, both depression and anxiety were reportedly higher among EC users. Impulsive behaviors, reported as impulsivity, were also found to be correlated with the adoption of EC use. However, there is a lack of evidence regarding the impact of EC use on mental health outcomes in children. This umbrella review highlights the urgent need to further explore the effects of current EC use from a psychiatric and public health perspective.