Electrocortical Reactivity during Self-Referential Processing Predicts the Development of Depression across Adolescence.

BACKGROUND: Negative attentional biases and self-schemas have been implicated in the development of depression. Research has indicated that a larger late positive potential (LPP) to negative self-referential words is associated with depression-as well as a maternal history of depression, an indicator of risk. However, it is unclear whether the LPP to self-referential words predicts the actual development of depression. The present study examined whether electrocortical reactivity during self-referential processing predicts the development of depression across adolescence. METHODS: The sample consisted of 165 8 to 14-year-old girls with no lifetime history of a depressive disorder who completed the self-referential encoding task (SRET) while electroencephalography was recorded at a baseline assessment. Participants and their parent completed the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children at the baseline, 2-year, 4-year, and 6-year follow-up assessments. RESULTS: Results indicated that a larger LPP to negative self-referential words at baseline predicted an increased likelihood of developing chronic-intermittent depression (i.e., persistent and/or recurrent), but not non-chronic, single episode depression, across adolescence. In contrast, neither SRET recall biases nor the LPP to positive self-referential words predicted the development of either type of depression. CONCLUSIONS: The present study suggests that electrocortical reactivity associated with a negative self-schema in late childhood predicts the development of a more pernicious subtype of depression across adolescence. Moreover, the present study highlights the importance of considering clinical course in the examination of biomarkers of risk for depression.

The LEADING Guideline: Reporting Standards for Expert Panel, Best-Estimate Diagnosis, and Longitudinal Expert All Data (LEAD) Studies.

Accurate assessments of symptoms and diagnoses are essential for health research and clinical practice but face many challenges. The absence of a single error-free measure is currently addressed by assessment methods involving experts reviewing several sources of information to achieve a more accurate or best-estimate assessment. Three bodies of work spanning medicine, psychiatry, and psychology propose similar assessment methods: The Expert Panel, the Best-Estimate Diagnosis, and the Longitudinal Expert All Data (LEAD). However, the quality of such best-estimate assessments is typically very difficult to evaluate due to poor reporting of the assessment methods and when it is reported, the reporting quality varies substantially. Here we tackle this gap by developing reporting guidelines for such studies, using a four-stage approach: 1) drafting reporting standards accompanied by rationales and empirical evidence, which were further developed with a patient organization for depression, 2) incorporating expert feedback through a two-round Delphi procedure, 3) refining the guideline based on an expert consensus meeting, and 4) testing the guideline by i) having two researchers test it and ii) using it to examine the extent previously published articles report the standards. The last step also demonstrates the need for the guideline: 18 to 58% (Mean = 33%) of the standards were not reported across fifteen randomly selected studies. The LEADING guideline comprises 20 reporting standards related to four groups: The Longitudinal design; the Appropriate data; the Evaluation - experts, materials, and procedures; and the Validity group. We hope that the LEADING guideline will be useful in assisting researchers in planning, reporting, and evaluating research aiming to achieve best-estimate assessments.

Examining the influence of episode number and age of onset on individual depressive symptoms across episodes of major depression.

Major depression is characterized by an episodic course with symptom manifestations differing across episodes. Previous work has found that symptom presentation differs across age. However, studies of symptom presentation have largely focused on symptoms in individual episodes, requiring further investigation of longitudinal symptom change. This study explored the impact of the initial age of onset, the number of episodes, and age of onset of each episode on individual depressive symptoms, while accounting for episode severity. We used data from the Oregon Adolescent Depression Project (N = 629) examining participants with at least one major depressive episode, assessed by diagnostic interview, across a 15-year follow-up. Multilevel logistic regression models revealed that approximately 20-25% of the main effects were significant and some were qualified by cross-level interactions. However, only a few associations remained robust after correcting for multiple comparisons. Specifically, older initial age of onset was associated with fatigue, younger initial age of onset for the first episode was associated with suicidal ideation, and a lower episode number was associated with weight loss. These findings highlight potential initial age of onset and scar effects influencing symptom manifestation, but require replication.

Cardiovascular Risk Estimation Is Suboptimal in People With HIV.

BACKGROUND: Established cardiovascular disease (CVD) risk prediction functions may not accurately predict CVD risk in people with HIV. We assessed the performance of 3 CVD risk prediction functions in 2 HIV cohorts. METHODS AND RESULTS: CVD risk scores were calculated in the Mass General Brigham and Kaiser Permanente Northern California HIV cohorts, using the American College of Cardiology/American Heart Association atherosclerotic CVD function, the FHS (Framingham Heart Study) hard coronary heart disease function and the Framingham Heart Study hard CVD function. Outcomes were myocardial infarction or coronary death for FHS hard coronary heart disease function; and myocardial infarction, stroke, or coronary death for American College of Cardiology/American Heart Association and FHS hard CVD function. We calculated regression coefficients and assessed discrimination and calibration by sex; predicted to observed risk of outcome was also compared. In the combined cohort of 9412, 158 (1.7%) had a coronary heart disease event, and 309 (3.3%) had a CVD event. Among women, CVD risk was generally underestimated by all 3 risk functions. Among men, CVD risk was underestimated by the American College of Cardiology/American Heart Association and FHS hard CVD function, but overestimated by the FHS hard coronary heart disease function. Calibration was poor for women using the FHS hard CVD function and for men using all functions. Discrimination in all functions was good for women (c-statistics ranging from 0.78 to 0.90) and moderate for men (c-statistics ranging from 0.71 to 0.72). CONCLUSIONS: Established CVD risk prediction functions generally underestimate risk in people with HIV. Differences in model performance by sex underscore the need for both HIV-specific and sex-specific functions. Development of CVD risk prediction models tailored to HIV will enhance care for aging people with HIV.

Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.

Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.

Case Report: Pediatric Thyroid Storm Presenting to the Emergency Department with Afebrile Seizure.

Introduction: Seizures are a common presenting complaint and account for approximately 1% of total emergency department (ED) visits. Seizures are especially common in children less than five years old as they have a lower seizure threshold as compared to adults. One potentially dangerous etiology that is far less common, especially in children, is thyroid storm, the extreme manifestation of hyperthyroidism. Case Report: We describe the case of a 3-year-old girl who presented to the ED with an afebrile seizure but was found to be in thyroid storm. This case should serve as a reminder for emergency physicians to consider thyroid disease when evaluating patients presenting with seizures. Conclusion: Although most pediatric seizures are self-limited and frequently benign, it is imperative that the emergency physician evaluate for and rule out any potentially associated dangerous conditions such as thyroid storm.

Irritability across adolescence: Examining longitudinal trajectory, stability, and associations with psychopathology and functioning at age 18.

BACKGROUND: Irritability, marked by diminished frustration tolerance, holds significant implications for youth mental health treatment. Despite prior research on irritability trajectories, understanding of individual differences during adolescence remains limited. This study examines the stability and trajectory of irritability across ages 12-18, investigating associations with psychopathology and functioning at age 18. METHODS: A community sample of families with 3-year-old children (N = 518) was recruited via commercial mailing lists. Irritability was assessed at ages 12, 15, and 18 using the Affective Reactivity Index. Psychopathology at age 18 was evaluated with the Kiddie Schedule for Affective Disorders and Schizophrenia, and functioning was assessed through the UCLA Life Stress Interview. Measurement invariance analyses and latent growth curve modeling were conducted within a structural equation modeling (SEM) framework. RESULTS: Configural, metric, and scalar invariance models were supported. Elevated irritability at age 12 predicted adverse outcomes at age 18, including increased psychotropic medication use, mental health treatment, suicidal ideation, self-injury, and psychiatric disorders. Importantly, these associations persisted even after accounting for corresponding variables at age 12. The trajectory of irritability during early adolescence significantly predicted heightened risks for various outcomes at age 18, including suicidal ideation, depression, anxiety, disruptive behavior disorders, and impaired interpersonal functioning. DISCUSSION: Limitations include using only youth-reported data at age 18, limited generalizability from a mostly White, middle-class sample, and insufficient exploration of the broader developmental trajectory of irritability. Nevertheless, the findings emphasize the crucial role of irritability's trajectory in influencing various psychopathological and functional outcomes in late adolescence.

The cortical representation of language timescales is shared between reading and listening.

Language comprehension involves integrating low-level sensory inputs into a hierarchy of increasingly high-level features. Prior work studied brain representations of different levels of the language hierarchy, but has not determined whether these brain representations are shared between written and spoken language. To address this issue, we analyze fMRI BOLD data that were recorded while participants read and listened to the same narratives in each modality. Levels of the language hierarchy are operationalized as timescales, where each timescale refers to a set of spectral components of a language stimulus. Voxelwise encoding models are used to determine where different timescales are represented across the cerebral cortex, for each modality separately. These models reveal that between the two modalities timescale representations are organized similarly across the cortical surface. Our results suggest that, after low-level sensory processing, language integration proceeds similarly regardless of stimulus modality.

The Prospective Predictive Power of Parent-Reported Personality Traits and Facets in First-Onset Depression in Adolescent Girls.

Certain personality traits and facets are well-known risk factors that predict first-onset depression during adolescence. However, prior research predominantly relied on self-reported data, which has limitations as a source of personality information. Reports from close informants have the potential to increase the predictive power of personality on first-onsets of depression in adolescents. With easy access to adolescents' behaviors across settings and time, parents may provide important additional information about their children's personality. The same personality trait(s) and facet(s) rated by selves (mean age 14.4 years old) and biological parents at baseline were used to prospectively predict depression onsets among 442 adolescent girls during a 72-month follow-up. First, bivariate logistic regression was used to examine whether parent-reported personality measures predicted adolescent girls' depression onsets; then multivariate logistic regression was used to test whether parent reports provided additional predictive power above and beyond self-reports of same trait or facet. Parent-reported personality traits and facets predicted adolescents' depression onsets, similar to findings using self-reported data. After controlling for the corresponding self-report measures, parent-reported higher openness (at the trait level) and higher depressivity (at the facet-level) incrementally predicted first-onset of depression in the sample. Findings demonstrated additional variance contributed by parent-reported personality measures and validated a multi-informant approach in using personality to prospectively predict onsets of depression in adolescent girls.

Early Predictors and Concurrent Correlates of Tonic and Phasic Irritability in Adolescence.

Irritability is a common presenting problem in youth mental health settings that is thought to include two components: tonic (e.g., irritable, touchy mood) and phasic (e.g., temper outbursts), each with unique correlates and outcomes, including later internalizing and externalizing problems, respectively. However, we are unaware of any studies of early predictors of tonic and phasic irritability. We utilized data from a longitudinal study of a community sample of 3-year-old children followed to age 15 (n = 444). We conducted confirmatory factor analysis (CFA) of items from several self-report irritability measures at age 15, including the Affective Reactivity Index, the International Personality Item Pool, the Schedule for Non-Adaptive and Adaptive Personality Youth Version, and the Child Depression Inventory, and examined their early childhood predictors. The CFA identified dimensions consistent with tonic and phasic irritability. Tonic irritability at age 15 was uniquely associated with concurrent internalizing disorders and suicidal behavior while phasic irritability was uniquely associated with concurrent externalizing disorders. When adolescent tonic and phasic irritability were examined together, female sex and parental depressive and substance use disorders at age 3 uniquely predicted adolescent tonic irritability. Additionally, male sex, less parental education, greater laboratory-observed anger and impulsivity, ODD symptoms, higher irritability, and no parental substance use history at age 3 uniquely predicted adolescent phasic irritability. Youth-reported tonic and phasic irritability at age 15 appear to be distinguishable constructs with distinct concurrent correlates and early antecedents. Findings have important implications for research on the etiology of irritability and developing effective treatments.

Emotion dynamics in current and remitted depression: an ecological momentary assessment study.

BACKGROUND: Individuals in a depressive episode and healthy controls exhibit robust differences on affect dynamics captured with ecological momentary assessment (EMA). However, few studies have explored affect dynamics in individuals in remission from depression, and results have been mixed. METHODS: A community sample of 18-year-olds (N = 345) completed diagnostic interviews and EMA probing emotions and low interest/motivation 5× daily for 2 weeks. Affect home base, variability, and inertia were compared across currently depressed, remitted, and never-depressed groups. RESULTS: Both depression groups had a higher negative affect (NA) and low interest/motivation home base, lower positive affect (PA) home base, greater variability of NA, PA, and low interest/motivation, and greater NA and low interest/motivation inertia than never-depressed participants. Additionally, the currently depressed group had a higher sad home base specifically, greater variability across most negative emotions and low interest/motivation, and greater low interest/motivation inertia than the remitted group. The currently depressed and remitted groups did not differ in anxious, upset, or PA home base, anxious or PA variability, and inertia of all negative emotions and PA. CONCLUSIONS: Findings suggest that a number of abnormalities in emotion and reward functioning persist after a depressive episode resolves, however, the tendency to experience higher levels of sadness, greater range of a variety of negative emotions, and more variable and persistent low interest/motivation are exacerbated during depressive episodes. Conversely, greater intensity and persistence of some negative emotions (anxiety, upset) and blunted positive emotions appear to equally characterize depression in both the symptomatic and remitted state.

Individual and joint effects of prenatal PM2.5 and maternal stress on child temperament.

Prenatal fine particulate matter (PM2.5) and maternal psychological functioning have been associated with child cognitive outcomes, though their independent and joint impacts on earlier behavioral outcomes remains less studied. We used data from 382 mother-child pairs from a prospective birth cohort in Mexico City. Temperament was measured at 24 months using the Carey Toddler Temperament Scale (TTS). Exploratory factor analysis (EFA) was used to update the factor structure of the TTS. During pregnancy, mothers completed the Crisis in Family Systems-Revised, Edinburgh Depression Scale, pregnancy-specific anxiety scale, and the Perceived Stress Scale. Pregnancy PM2.5 was assessed using estimates from a satellite-based exposure model. We assessed the association between prenatal maternal stress and PM2.5 on temperament, in both independent and joint models. Quantile g-computation was used to estimate the joint associations. Models were adjusted for maternal age, SES, education, child sex, and child age. In EFA, we identified three temperament factors related to effortful control, extraversion, and negative affect. Our main results showed that higher levels of PM2.5 and several of the maternal psychological functioning measures were related to both effortful control and negative affect in the child, both individually and as a mixture. For instance, a one quartile increase in the prenatal mixture was associated with higher negative affect scores in the child (0.34, 95% CI: 0.16, 0.53). We observed modification of these associations by maternal SES, with associations seen only among lower SES participants for both effortful control (-0.45, 95% CI: -0.70, -0.20) and negative affect outcomes (0.60, 95% CI: 0.35, 0.85). Prenatal PM2.5 and maternal psychological functioning measures were associated with toddler temperament outcomes, providing evidence for impacts of chemical and non-chemical stressors on early child health.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Association between prenatal and childhood PM2.5 exposure and preadolescent anxiety and depressive symptoms.

Background: Fine particulate matter (PM2.5) exposure has been linked to anxiety and depression in adults; however, there is limited research in the younger populations, in which symptoms often first arise. Methods: We examined the association between early-life PM2.5 exposure and symptoms of anxiety and depression in a cohort of 8-11-year-olds in Mexico City. Anxiety and depressive symptoms were assessed using the Spanish versions of the Revised Children's Manifest Anxiety Scale and Children's Depression Inventory. Daily PM2.5 was estimated using a satellite-based exposure model and averaged over several early and recent exposure windows. Linear and logistic regression models were used to estimate the change in symptoms with each 5-µg/m3 increase in PM2.5. Models were adjusted for child's age, child's sex, maternal age, maternal socioeconomic status, season of conception, and temperature. Results: Average anxiety and depressive symptom T-scores were 51.0 (range 33-73) and 53.4 (range 44-90), respectively. We observed consistent findings for exposures around the fourth year of life, as this was present for both continuous and dichotomized anxiety symptoms, in both independent exposure models and distributed lag modeling approaches. This window was also observed for elevated depressive symptoms. An additional consistent finding was for PM2.5 exposure during early pregnancy in relation to both clinically elevated anxiety and depressive symptoms, this was seen in both traditional and distributed lag modeling approaches. Conclusion: Both early life and recent PM2.5 exposure were associated with higher mental health symptoms in the child highlighting the role of PM2.5 in the etiology of these conditions.

Irritability in Youths: A Critical Integrative Review.

Irritability, defined as proneness to anger that may impair an individual's functioning, is common in youths. There has been a recent upsurge in relevant research. The authors combine systematic and narrative review approaches to integrate the latest clinical and translational findings and provide suggestions for addressing research gaps. Clinicians and researchers should assess irritability routinely, and specific assessment tools are now available. Informant effects are prominent, are stable, and vary by age and gender. The prevalence of irritability is particularly high among individuals with attention deficit hyperactivity disorder, autism spectrum disorder, and mood and anxiety disorders. Irritability is associated with impairment and suicidality risk independent of co-occurring diagnoses. Developmental trajectories of irritability (which may begin early in life) have been identified and are differentially associated with clinical outcomes. Youth irritability is associated with increased risk of anxiety, depression, behavioral problems, and suicidality later in life. Irritability is moderately heritable, and genetic associations differ based on age and comorbid illnesses. Parent management training is effective for treating psychological problems related to irritability, but its efficacy in treating irritability should be tested rigorously, as should novel mechanism-informed interventions (e.g., those targeting exposure to frustration). Associations between irritability and suicidality and the impact of cultural context are important, underresearched topics. Analyses of large, diverse longitudinal samples that extend into adulthood are needed. Data from both animal and human research indicate that aberrant responses to frustration and threat are central to the pathophysiology of irritability, revealing important translational opportunities.

Inside "Operation Change Agent": Mallinckrodt's Plan for Capturing the Opioid Market.

CONTEXT: The United States is deeply entangled in an opioid crisis that began with the overuse of prescription painkillers. At the height of the prescription opioid crisis (2006-2012), Mallinckrodt Pharmaceuticals was the largest opioid manufacturer. This study explores Mallinckrodt strategies to expand its market share by promoting a new opioid. METHODS: Using the Opioids Industry Document Archive, we analyzed the incentive structures, sales contests, and rhetorical strategy behind Mallinckrodt's "Operation Change Agent," a campaign to switch patients from OxyContin to Mallinckrodt-branded painkillers. A structured search of the archive in October 2022 retrieved 464 documents dated between 2010 and 2020. FINDINGS: We identified a range of sales force motivational techniques, including hypertargeting high-decile prescribers, the provision of free trial kits, using emotion-based language to connect with prescribers, and strategies to oppose prescriber resistance. Throughout, managers used specific incentivization metaphors to frame strategies through sport and ultramarathons. CONCLUSIONS: This research on internal corporate strategy adds to growing challenges to industry claims that opioid sales teams simply educated providers and helped fill existing demand for their products. Moreover, this research has important implications for regulatory policy and consumer protections that can better protect health in the face of competitive market forces.

Parent and Teacher Ratings of Tonic and Phasic Irritability in a Clinical Sample.

Research on tonic (persistently angry or grumpy mood) and phasic (temper tantrums/outbursts) irritability in youth has utilized community samples and information from parents and youth. We examined whether tonic and phasic irritability are empirically distinguishable and have similar correlates using teacher, in addition to parent, reports in a clinical sample of children and adolescents. The sample included youth aged 5-18 evaluated at a university outpatient clinic, with complete information from 2481 parents and 2449 teachers. We conducted confirmatory factor analysis (CFA) using items from several parent- and teacher-report inventories and examined concurrent associations with psychopathology and functioning. The CFA supported a two-factor model consistent with tonic and phasic irritability in both parent- and teacher-reports. Parent-reported tonic irritability was associated with higher rates of depression and anxiety disorders, suicidality, and antidepressant medication use. Teacher-reported tonic irritability was associated with elevated rates of depression and antidepressant use. Both parent- and teacher-reported phasic irritability were linked to higher rates of ADHD combined type, oppositional defiant/conduct disorders, and referral for rages. Parent- and teacher-reported tonic and phasic irritability were all associated with impaired social functioning. Parents and teachers can distinguish tonic and phasic irritability, which are associated with internalizing and externalizing problems, respectively. Findings were generally consistent across informants, and with prior studies using community samples.

Neural response to monetary and social rewards and familial risk for psychopathology in adolescent females.

BACKGROUND: Adolescence is a key developmental period for the emergence of psychopathology. Reward-related brain activity increases across adolescence and has been identified as a potential neurobiological mechanism of risk for different forms of psychopathology. The reward positivity (RewP) is an event-related potential component that indexes reward system activation and has been associated with both concurrent and family history of psychopathology. However, it is unclear whether the RewP is also associated with higher-order psychopathology subfactors and whether this relationship is present across different types of reward. METHODS: In a sample of 193 adolescent females and a biological parent, the present study examined the association between adolescent and parental psychopathology subfactors and adolescent RewP to monetary and social reward. RESULTS: Results indicated that the adolescent and parental distress subfactors were negatively associated with the adolescent domain-general RewP. The adolescent and parental positive mood subfactors were negatively associated with the adolescent domain-general and domain-specific monetary RewP, respectively. Conversely, the adolescent and parental fear/obsessions subfactors were positively associated with the adolescent domain-general RewP. The associations between parental and adolescent psychopathology subfactors and the adolescent RewP were independent of each other. CONCLUSIONS: The RewP in adolescent females is associated with both concurrent and parental psychopathology symptoms, suggesting that it indexes both severity and risk for higher-order subfactors.

Adolescents' Sexual Orientation and Behavioral and Neural Reactivity to Peer Acceptance and Rejection: The Moderating Role of Family Support.

Sexual-minority adolescents frequently endure peer rejection, yet scant research has investigated sexual-orientation differences in behavioral and neural reactions to peer rejection and acceptance. In a community sample of adolescents approximately 15 years old (47.2% female; same-sex attracted: n = 36, exclusively other-sex attracted: n = 310), we examined associations among sexual orientation and behavioral and neural reactivity to peer feedback and the moderating role of family support. Participants completed a social-interaction task while electroencephalogram data were recorded in which they voted to accept/reject peers and, in turn, received peer acceptance/rejection feedback. Compared with heterosexual adolescents, sexual-minority adolescents engaged in more behavioral efforts to ingratiate after peer rejection and demonstrated more blunted neural reactivity to peer acceptance at low, but not medium or high, levels of family support. By using a simulated real-world social-interaction task, these results demonstrate that sexual-minority adolescents display distinct behavioral and neural reactions to peer acceptance and rejection.

Associations between a metal mixture and infant negative affectivity: Effect modification by prenatal cortisol and infant sex.

In-utero exposures interact in complex ways that influence neurodevelopment. Animal research demonstrates that fetal sex moderates the impact of joint exposure to metals and prenatal stress measures, including cortisol, on offspring socioemotional outcomes. Further research is needed in humans. We evaluated the joint association of prenatal exposures to a metal mixture and cortisol with infant negative affectivity, considering sex differences. Analyses included 226 (29% White, Non-Hispanic) mother-infant pairs with data on exposures and negative affectivity assessed using the Infant Behavior Questionnaire-Revised in 6-month-olds. Results showed that girls whose mothers had higher cortisol had significantly higher scores of Fear and Sadness with greater exposure to the mixture. Examining higher-order interactions may better elucidate the effects of prenatal exposure to metals and cortisol on socioemotional functioning.