Faculty Bibliography

Last year, we wrote to you of our dedication and vision for this journal "to be antiracist at every level," outlining the following 6 initiatives "to reshape the Journal to pursue this vision:" (1) Issuing a Call for Papers "on racism and its impacts on child development and children's mental health;" (2) updating our Guide for Authors "to emphasize that we will evaluate articles submitted to the Journal on whether their study designs and discussions consider and address human diversity in the context of their research questions and hypotheses; (3) assembling a special collection of "Journal articles on bias, bigotry, racism, and mental health disparities;" (4) accelerating "our efforts to make our editorial board inclusive and representative of our community of scientists and practitioners as well as the communities we all serve;" (5) engaging in "continuing education and dialogue as an Editorial Board that will include antiracism training;" and (6) critically examining "our editorial and peer review process to ensure it is antiracist.¹ In this Editors' Note, we write to update you on our progress.

BACKGROUND:Climate change has important implications for the health and futures of children and young people, yet they have little power to limit its harm, making them vulnerable to climate anxiety. This is the first large-scale investigation of climate anxiety in children and young people globally and its relationship with perceived government response. METHODS:We surveyed 10 000 children and young people (aged 16-25 years) in ten countries (Australia, Brazil, Finland, France, India, Nigeria, Philippines, Portugal, the UK, and the USA; 1000 participants per country). Invitations to complete the survey were sent via the platform Kantar between May 18 and June 7, 2021. Data were collected on participants' thoughts and feelings about climate change, and government responses to climate change. Descriptive statistics were calculated for each aspect of climate anxiety, and Pearson's correlation analysis was done to evaluate whether climate-related distress, functioning, and negative beliefs about climate change were linked to thoughts and feelings about government response. FINDINGS/RESULTS:Respondents across all countries were worried about climate change (59% were very or extremely worried and 84% were at least moderately worried). More than 50% reported each of the following emotions: sad, anxious, angry, powerless, helpless, and guilty. More than 45% of respondents said their feelings about climate change negatively affected their daily life and functioning, and many reported a high number of negative thoughts about climate change (eg, 75% said that they think the future is frightening and 83% said that they think people have failed to take care of the planet). Respondents rated governmental responses to climate change negatively and reported greater feelings of betrayal than of reassurance. Climate anxiety and distress were correlated with perceived inadequate government response and associated feelings of betrayal. INTERPRETATION/CONCLUSIONS:Climate anxiety and dissatisfaction with government responses are widespread in children and young people in countries across the world and impact their daily functioning. A perceived failure by governments to respond to the climate crisis is associated with increased distress. There is an urgent need for further research into the emotional impact of climate change on children and young people and for governments to validate their distress by taking urgent action on climate change. FUNDING/BACKGROUND:AVAAZ.

In response to the COVID-19 pandemic, research institutions across the globe have modified their operations in ways that have limited or eliminated the amount of permissible in-person research interaction. In order to prevent the loss of important developmentally-timed data during the pandemic, researchers have quickly pivoted and developed innovative methods for remote assessment of research participants. In this manuscript, we describe methods developed for remote assessment of a parent child cohort with a focus on examining the perinatal environment, behavioral and biological indicators of child neurobehavioral development, parent-child interaction, as well as parent and child mental and physical health. We include recommendations relevant to adapting in-laboratory assessments for remote data collection and conclude with a description of the successful dissemination of the methods to eight research sites across the United States, each of whom are involved in Phase 1 of the HEALthy Brain and Child Development (HBCD) Study. These remote methods were born out of pandemic-related necessity; however, they have much wider applicability and may offer advantages over in-laboratory neurodevelopmental assessments.

Introduction: Peripheral T-cell lymphomas (PTCLs) include heterogeneous entities of rare and aggressive neoplasms. The improved understanding of the biological/molecular mechanisms driving T-cell transformation and tumor maintenance has powerfully propelled new therapeutic programs. However, despite this progress, PTCLs remain an unmet medical need. Recurrent aberrations and the deregulated activation of distinct signaling pathways have been mapped and linked to selective subtypes. The JAK/STAT signaling pathway's deregulated activation plays a pathogenetic role in PTCL, including ALCL subtypes. STATs regulate the differentiation/phenotype, survival and cell-growth, metabolism, and drug resistance of T-cell lymphomas as well as host immunosuppressive microenvironments. Although many drugs' discovery programs were launched, a plethora of compounds has failed.
Method(s): We have discovered heterobifunctional molecules by an iterative medicinal chemistry SAR campaign that potently and selectively degrade STAT3 in a proteasome-dependent manner. Conventional PTCL cell lines and Patient Derived Tumor Xenograft (PDTX) and/or derived cell lines (PDTX-CL), carrying either WT- or mutated-STAT3, were exposed to increasing amounts (50nM5microM) of STAT3-degraders. Proteins and mRNA transcripts (2144hrs) were assessed by deep-proteomics and paired-end RNA sequencing, combined with WB/flow cytometry and qRT-PCR. Cell-titer-glo, cell titer blue, Annexin-V and S-cell cycle analyses were used as readouts. Chromatin accessibility, STAT3 DNA binding, 3D chromosomal architecture reorganization and 5-hmC profiling were assessed by ATACseq, CHIPseq and Hi-C and H3K27ac Hi-CHIP and mass-spectrometry. Drug testing/discovery combinations (96-well-plate) were performed using a semi-automated flow-cytometry. A battery of PTCL PDTX models were tested in pre-clinical trials.
Result(s): Treatment of ALK+ ALCL (SU-DHL1) led to the rapid (~6hrs.) and profound down-regulation of STAT3 followed by the loss of canonical STAT3-regulated proteins (SOCS3, MYC, Granzyme B, GAS1, and IL2RA), without appreciable changes for other STAT family members (STAT1, STAT5b). In vitro, cytoplasmic, nuclear, and mitochondrial STAT3 downregulation was maintained up to 144 hrs. Loss of STAT3 in ALK+/- ALCL and BIA-ALCL cells was associated with major transcriptional changes (7116-10615 and 15114 DEGs in ALK- and ALK+ ALCL, respectively), underscoring public/shared as well as private time-dependent signatures. Main down-regulated pathways included JAK-STAT, MAPK, NF-kB, PI3K, TGFb, and TNFa. Comparison of STAT3 shRNA (ALK+ ALCL) and STAT3 degrader (ALK-/ALK+ ALCL) signatures demonstrated a substantial and concordant gene modulation (24hrs) among all models with the highest overlaps between ALK+ ALCL (Figure 3). To identify direct STAT3 gene targets, we analyzed CHIPseq peaks and predicted bindings sites, demonstrating that canonical genes, i.e., SOCS3, Granzyme B, GAS1, IL2RA, STAT3, and CD30, were significantly downregulated. Conversely, CD58, CD274, and MCH-I/II were upregulated at late time points. By mapping the STAT3 binding sites in ALK+ and ALK- ALCL, we have identified 1077 and 2763 STAT3 peaks within promoter/5'-/3'- and distant intergenic regions, corresponding to both coding and non-coding genes. Therapeutically, in vitro treatments led to cell cycle arrest and profound growth inhibition, and over time increased cell death of PTCL cells, including ALCL. Accordingly, growth inhibition of ALCL xenograft and PDTX tumors was also achieved (Figure 2). To identify drugs that could synergize withSTAT3-degrader activity, we tested a compound library (40) targeting pro-tumorigenic PTCL pathways as well as FDA-approved compounds. Ongoing studies are in progress.
Conclusion(s): We have discovered selective STAT3 degraders which control PTCL growth. STAT3 degraders are powerful tools to define the STAT3 pathogenetic mechanisms and dissect genes/pathways to be targeted for T-cell lymphoma eradication. These data provide additional rationale for testing STAT3 degraders in the clinic for the treatment of aggressive malignancies including PTCL/ALCL. [Formula presented] Disclosures: Yang: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dey: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karnik: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Elemento: Owkin: Consultancy, Other: Current equity holder; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; Johnson and Johnson: Research Funding; Eli Lilly: Research Funding; Janssen: Research Funding; Champions Oncology: Consultancy; Freenome: Consultancy, Other: Current equity holder in a privately-held company; One Three Biotech: Consultancy, Other: Current equity holder; AstraZeneca: Research Funding. Horwitz: Affimed: Research Funding; Aileron: Research Funding; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. DeSavi: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.
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BACKGROUND:Previous studies have suggested that social media data, along with machine learning algorithms, can be used to generate computational mental health insights. These computational insights have the potential to support clinician-patient communication during psychotherapy consultations. However, how clinicians perceive and envision using computational insights during consultations has been underexplored. OBJECTIVE:The aim of this study is to understand clinician perspectives regarding computational mental health insights from patients' social media activities. We focus on the opportunities and challenges of using these insights during psychotherapy consultations. METHODS:We developed a prototype that can analyze consented patients' Facebook data and visually represent these computational insights. We incorporated the insights into existing clinician-facing assessment tools, the Hamilton Depression Rating Scale and Global Functioning: Social Scale. The design intent is that a clinician will verbally interview a patient (eg, How was your mood in the past week?) while they reviewed relevant insights from the patient's social media activities (eg, number of depression-indicative posts). Using the prototype, we conducted interviews (n=15) and 3 focus groups (n=13) with mental health clinicians: psychiatrists, clinical psychologists, and licensed clinical social workers. The transcribed qualitative data were analyzed using thematic analysis. RESULTS:Clinicians reported that the prototype can support clinician-patient collaboration in agenda-setting, communicating symptoms, and navigating patients' verbal reports. They suggested potential use scenarios, such as reviewing the prototype before consultations and using the prototype when patients missed their consultations. They also speculated potential negative consequences: patients may feel like they are being monitored, which may yield negative effects, and the use of the prototype may increase the workload of clinicians, which is already difficult to manage. Finally, our participants expressed concerns regarding the prototype: they were unsure whether patients' social media accounts represented their actual behaviors; they wanted to learn how and when the machine learning algorithm can fail to meet their expectations of trust; and they were worried about situations where they could not properly respond to the insights, especially emergency situations outside of clinical settings. CONCLUSIONS:Our findings support the touted potential of computational mental health insights from patients' social media account data, especially in the context of psychotherapy consultations. However, sociotechnical issues, such as transparent algorithmic information and institutional support, should be addressed in future endeavors to design implementable and sustainable technology.

Odor perception can both evoke emotional states and be shaped by emotional or hedonic states. The amygdala complex plays an important role in recognition of, and response to, hedonically valenced stimuli, and has strong, reciprocal connectivity with the primary olfactory (piriform) cortex. Here, we used differential odor-threat conditioning in rats to test the role of basolateral amygdala (BLA) input to the piriform cortex in acquisition and expression of learned olfactory threat responses. Using local field potential recordings, we demonstrated that functional connectivity (high gamma band coherence) between the BLA and posterior piriform cortex (pPCX) is enhanced after differential threat conditioning. Optogenetic suppression of activity within the BLA prevents learned threat acquisition, as do lesions of the pPCX prior to threat conditioning (without inducing anosmia), suggesting that both regions are critical for acquisition of learned odor threat responses. However, optogenetic BLA suppression during testing did not impair threat response to the CS+ , but did induce generalization to the CS-. A similar loss of stimulus control and threat generalization was induced by selective optogenetic suppression of BLA input to pPCX. These results suggest an important role for amygdala-sensory cortical connectivity in shaping responses to threatening stimuli.

BACKGROUND:Despite increasing prevalence of nonmedical ketamine use globally, data on ketamine use disorders, which are classified in the DSM-5 under criteria for phencyclidine, are limited. This study assessed the reliability and applicability of DSM-based diagnostic criteria for ketamine use disorder. METHODS:Participants who used ecstasy were recruited through the Tri-City Study of Club Drug Use, Abuse, and Dependence in St. Louis, Miami, and Sydney. Those who reported using ketamine (lifetime use >5 times) were included in these analyses (n = 205). Participants were interviewed using the computerized Substance Abuse Module for Club Drugs (CD-SAM) at baseline and 7 days later for the reliability of diagnoses and individual diagnostic criteria. RESULTS:Overall, 29.3% met DSM-5 adopted criteria for ketamine use disorder at Time 1. Moderate to excellent test-retest reliability was observed consistently across study sites for any ketamine use disorder (κ = 0.57, Y = 0.61) and severe ketamine use disorder (κ = 0.62, Y = 0.79). Continued use of ketamine despite knowledge of physical or psychological problems was the most frequently endorsed individual criterion (59.0%), followed by reported withdrawal (30.2%) and physically hazardous use (29.8%). All individual criteria had acceptable reliability estimates (κ ≥ 0.41). CONCLUSIONS:Diagnoses of ketamine use disorder can be reliably evaluated using this fully structured diagnostic instrument's questions and algorithm. Ketamine-related withdrawal among people who use ketamine should be re-evaluated. Considering that after-effects of this dissociative anesthetic can last for many hours, it is important to explore a different timeframe for possible withdrawal effects.

The high co-occurrence of intimate partner violence (IPV) and physical child abuse suggests that studying these forms of aggression simultaneously, bidirectionally, and longitudinally is critical. Guided by family systems theory, this study examined parent-child aggression (PCA) risk, IPV victimization, and child behavior problems as reported by mothers and fathers when their child was 18 months and at 4 years old, to evaluate whether negative processes can transmit across family subsystems (i.e., spillover hypothesis) and/or across individuals (i.e., crossover hypothesis). Results indicated that mothers' PCA risk predicted their subsequent IPV victimization and their reported child behavior problems (i.e., spillover effects) as well as fathers' reported IPV victimization (i.e., crossover effect). Maternal reports of child behavior problems also predicted mothers' reported IPV victimization and fathers' reported child behavior problems, indicating child-driven effects. Overall, mothers rather than fathers appear more vulnerable to harmful spillover effects. Findings underscore the need for early prevention and intervention given the complex, transactional nature of family violence.