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Post-instrument covariates are often included as controls in instrumental variable (IV) analyses to address a violation of the exclusion restriction. However, we show that such analyses are subject to biases unless strong assumptions hold. Using linear constant-effects models, we present asymptotic bias formulas for three estimators (with and without measurement error): IV with post-instrument covariates, IV without post-instrument covariates, and ordinary least squares. In large samples and when the model provides a reasonable approximation, these formulas sometimes allow the analyst to bracket the parameter of interest with two estimators and allow the analyst to choose the estimator with the least asymptotic bias. We illustrate these points with a discussion of the settler mortality IV used by Acemoglu, Johnson, and Robinson.

Introduction: Mu opioid receptor gene (OPRM1) variant rs1799971 introduces a CpG site, which may influence DNA methylation (DNAm) and opioid/pain outcomes. Objectives: In this nested analysis, we investigated both OPRM1 A118G genotype and promoter/immediate downstream blood DNAm sequencing data for associations with opioid effects and chronic postsurgical pain (CPSP) in a surgical cohort. Methods: Prospectively recruited opioid naïve patients undergoing Nuss procedure or spinal fusion with rs1799971 genotypes (Illumina arrays), DNAm (next generation enzymatic methylation sequencing at Chr6:154,039,209-154,039,803) and outcomes—opioid analgesia (integrated opioid use 1 pain over postoperative days 0 and 1 normalized to surgery type), safety—respiratory depression (RD) in high opioid use groups, and CPSP (Numerical Rating Scale .3/10 2-12 months postsurgery)—were included. Linear and logistic regression were performed to test genetic and epigenetic associations, adjusted for sociodemographics, cell types, and analgesics. Results: In this cohort (N 5 112; 15.3 6 2.0 years, 50% female, 83% White, 55% had CPSP, 13% had RD), DNAm at Chr6: 154039216-154039217 was associated with CPSP (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.00-1.57; P 5 0.03), Chr6: 154039661-154039662 with acute integrated pain (b 5 220.9, 95% CI, 240.70 to 21.10, P 5 0.04), Chr6:154039520-154039521 (OR, 1.49; 95% CI, 1.09-2.03; P 5 0.01), and Chr6:154039571-154039572 (OR, 1.47; 95% CI, 1.08-2.01; P 5 0.02) with RD. Significant CpG sites were located in Repressed Polycomb chromatin states. Genotype was not associated with DNAm or outcomes. Conclusion: Our analyses support OPRM1 DNAm as predictors of acute and chronic pain/opioid outcomes in children after painful surgery. Study limitations included absent GG genotype, low sequencing coverage, and lack of correction for multiple testing.

BACKGROUND: Unpredictable childhood experiences are an understudied form of early life adversity that impacts neurodevelopment in a sex-specific manner. The neurobiological processes by which exposure to early-life unpredictability impacts development and vulnerability to psychopathology remain poorly understood. The present study investigates the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala. METHODS: Participants included 150 youth (54% female). Early life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in a task-fMRI scan between the ages of 8 and 17 (223 total observations) measuring BOLD responses to novel and familiar scenes. RESULTS: Exposure to early-life unpredictability associated with BOLD contrast (novel vs. familiar) in a sex-specific manner. For males, but not females, higher QUIC scores were associated with lower BOLD activation in response to novel vs. familiar stimuli in the hippocampal head and amygdala. Secondary psychophysiological interaction (PPI) analyses revealed complementary sex-specific associations between QUIC and condition-specific functional connectivity between the right and left amygdala, as well as between the right amygdala and hippocampus bilaterally. CONCLUSION: Exposure to unpredictability in early life has persistent implications for the functional operations of limbic circuits. Importantly, consistent with emerging experimental animal and human studies, the consequences of early life unpredictability differ for males and females. Further, impacts of early-life unpredictability were independent of other risk factors including lower household income and negative life events, indicating distinct consequences of early-life unpredictability over and above more commonly studied types of early life adversity.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) impacts both individual and relational functioning. Veteran couples are at increased risk of relationship distress due to military stressors such as deployment, family reintegration, and traumatic stress. Although both Cognitive-Behavioral Conjoint Therapy (CBCT) and its brief version (bCBCT) consistently have large effects on reducing PTSD symptoms, these treatments have more variable effects on relational outcomes. Given the impact of relationship functioning on the overall health of veterans, improving the effect of PTSD treatments on relationship functioning is an essential area of research. One promising path is the role of MDMA (3,4-methylenedioxymethamphetamine)-assisted therapy in augmenting the relational impact of established therapeutic interventions such as bCBCT. METHOD/DESIGN: This is a single site, open-label study assessing the preliminary efficacy, safety, and acceptability of MDMA-assisted therapy in combination with bCBCT in 8 veterans with PTSD and their intimate partners (N = 16). Therapy teams trained in bCBCT and MDMA-assisted therapy will deliver bCBCT combined with two MDMA sessions and two couple emotion focused integration sessions. PTSD symptom severity and relationship functioning outcomes will be evaluated. CONCLUSION: This is the first study to examine the efficacy of MDMA-assisted bCBCT for improving PTSD and relationship functioning among a sample of U.S. military veterans and their partners. This project could provide an opportunity to pilot a scalable model of treating PTSD within the Veterans Affairs healthcare system and leverage the benefits of MDMA for veterans with PTSD, as well as the downstream benefits to their partner on both individual and relationship functioning. ClinicalTrials.gov Identifier: NCT05979844.

Adverse early-life experiences (ELA) affect a majority of the worlds children. Whereas the enduring impact of ELA on cognitive and emotional health is established, there are no tools to predict vulnerability to ELA consequences in an individual child. Epigenetic markers including peripheral-cell DNA-methylation profiles may encode ELA and provide predictive outcome markers, yet the interindividual variance of the human genome and rapid changes in DNA methylation in childhood pose significant challenges. Hoping to mitigate these challenges we examined the relation of several ELA dimensions to DNA methylation changes and outcome using a within-subject longitudinal design and a high methylation-change threshold. DNA methylation was analyzed in buccal swab/saliva samples collected twice (neonatally and at 12 months) in 110 infants. We identified CpGs differentially methylated across time for each child and determined whether they associated with ELA indicators and executive function at age 5. We assessed sex differences and derived a sex-dependent impact score based on sites that most contributed to methylation changes. Changes in methylation between two samples of an individual child reflected age-related trends and correlated with executive function years later. Among tested ELA dimensions and life factors including income to needs ratios, maternal sensitivity, body mass index and infant sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, high early-life unpredictability interacted with methylation changes to presage executive function. Thus, longitudinal, within-subject changes in methylation profiles may provide a signature of ELA and a potential predictive marker of individual outcome.

High unpredictability has emerged as a dimension of early-life adversity that may contribute to a host of deleterious consequences later in life. Early-life unpredictability affects development of limbic and reward circuits in both rodents and humans, with a potential to increase sensitivity to stressors and mood symptoms later in life. Here, we examined the extent to which unpredictability during childhood was associated with changes in mood symptoms (anhedonia and general depression) after two adult life stressors, combat deployment and civilian reintegration, which were assessed ten years apart. We also examined how perceived stress and social support mediated and /or moderated links between childhood unpredictability and mood symptoms. To test these hypotheses, we leveraged the Marine Resiliency Study, a prospective longitudinal study of the effects of combat deployment on mental health in Active-Duty Marines and Navy Corpsman. Participants (N = 273) were assessed for depression and anhedonia before (pre-deployment) and 3-6 months after (acute post-deployment) a combat deployment. Additional assessment of depression and childhood unpredictability were collected 10 years post-deployment (chronic post-deployment). Higher childhood unpredictability was associated with higher anhedonia and general depression at both acute and chronic post-deployment timepoints (βs ≥ 0.16, ps ≤.007). The relationship between childhood unpredictability and subsequent depression at acute post-deployment was partially mediated by lower social support (b = 0.07, 95% CI [0.03, 0.15]) while depression at chronic post-deployment was fully mediated by a combination of lower social support (b = 0.14, 95% CI [0.07, 0.23]) and higher perceived stress (b = 0.09, 95% CI [0.05, 0.15]). These findings implicate childhood unpredictability as a potential risk factor for depression in adulthood and suggest that increasing the structure and predictability of childhood routines and developing social support interventions after life stressors could be helpful for preventing adult depression.

BackgroundAnhedonia, an impairment in the motivation for or experience of pleasure, is a well-established transdiagnostic harbinger and core symptom of mental illness. Given increasing recognition of early life origins of mental illness, we posit that anhedonia should, and could, be recognized earlier if appropriate tools were available. However, reliable diagnostic instruments prior to childhood do not currently exist.MethodsWe developed an assessment instrument for anhedonia/reward processing in infancy, the Infant Hedonic/Anhedonic Processing Index (HAPI-Infant). Exploratory factor and psychometric analyses were conducted using data from 6- and 12-month-old infants from two cohorts (N = 188, N = 212). Then, associations were assessed between infant anhedonia and adolescent self-report of depressive symptoms.ResultsThe HAPI-Infant (47-items), exhibited excellent psychometric properties. Higher anhedonia scores at 6 (r = 0.23, p

BackgroundThe effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults both overall, and in relation, to sociodemographic characteristics.MethodsWe examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance.ResultsAge was associated with several metrics of dampened RAR; women had stronger and more robust RAR vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P

We have reconstructed baseline δ15N and δ13C of export production at Kingman Reef in the Central Equatorial Pacific (CEP) at sub-decadal resolution, nearly continuously over the last 2000 years. The changes in δ15N reflects the strength of the North Equatorial Counter Current (NECC) relative to the South Equatorial Current (SEC), and to a lesser extent, the North Equatorial Current (NEC). Seasonal to multi-decadal variation in the strength of these currents, through the redistribution of heat, have global climate impacts and influence marine and terrestrial ecosystems. We use modern El Niño-La Nina dynamics and the Tropical Pacific Decadal Variability (TPDV) pattern, which is defined in the CEP, as a framework for analyzing the isotopic data. The CEP δ15N and δ13C records exhibit multi-decadal (50-60 year) variability consistent with TPDV. A large multi-centennial feature in the CEP δ15N data, within age-model uncertainties, is consistent with one of the prolonged dry-pluvial sequences in the American west at the end of the Medieval Climate Anomaly, where low TPDV is correlated with drier conditions. This unique record shows that the strength of the NECC, as reflected in baseline δ15N and δ13C, has at quasi-predictable intervals throughout the late Holocene, toggled the phytoplankton community between prokaryotes and picoplankton versus eukaryotes.

BackgroundPatterns of sensory inputs early in life play an integral role in shaping the maturation of neural circuits, including those implicated in emotion and cognition. In both experimental animal models and observational human research, unpredictable sensory signals have been linked to aberrant developmental outcomes, including poor memory and effortful control. These findings suggest that sensitivity to unpredictable sensory signals is conserved across species and sculpts the developing brain. The current study provides a novel investigation of unpredictable maternal sensory signals in early life and child internalizing behaviors. We tested these associations in three independent cohorts to probe the generalizability of associations across continents and cultures.MethodThe three prospective longitudinal cohorts were based in Orange, USA (n = 163, 47.2 % female, Mage = 1 year); Turku, Finland (n = 239, 44.8 % female, Mage = 5 years); and Irvine, USA (n = 129, 43.4 % female, Mage = 9.6 years). Unpredictability of maternal sensory signals was quantified during free-play interactions. Child internalizing behaviors were measured via parent report (Orange & Turku) and child self-report (Irvine).ResultsEarly life exposure to unpredictable maternal sensory signals was associated with greater child fearfulness/anxiety in all three cohorts, above and beyond maternal sensitivity and sociodemographic factors. The association between unpredictable maternal sensory signals and child sadness/depression was relatively weaker and did not reach traditional thresholds for statistical significance.LimitationsThe correlational design limits our ability to make causal inferences.ConclusionsFindings across the three diverse cohorts suggest that unpredictable maternal signals early in life shape the development of internalizing behaviors, particularly fearfulness and anxiety.

BACKGROUND: Fetal exposure to maternal mood dysregulation influences child cognitive and emotional development, which may have long-lasting implications for mental health. However, the neurobiological alterations associated with this dimension of adversity have yet to be explored. Here, we tested the hypothesis that fetal exposure to entropy, a novel index of dysregulated maternal mood, would predict the integrity of the salience network, which is involved in emotional processing. METHODS: A sample of 138 child-mother pairs (70 females) participated in this prospective longitudinal study. Maternal negative mood level and entropy (an index of variable and unpredictable mood) were assessed 5 times during pregnancy. Adolescents engaged in a functional magnetic resonance imaging task that was acquired between 2 resting-state scans. Changes in network integrity were analyzed using mixed-effect and latent growth curve models. The amplitude of low frequency fluctuations was analyzed to corroborate findings. RESULTS: Prenatal maternal mood entropy, but not mood level, was associated with salience network integrity. Both prenatal negative mood level and entropy were associated with the amplitude of low frequency fluctuations of the salience network. Latent class analysis yielded 2 profiles based on changes in network integrity across all functional magnetic resonance imaging sequences. The profile that exhibited little variation in network connectivity (i.e., inflexibility) consisted of adolescents who were exposed to higher negative maternal mood levels and more entropy. CONCLUSIONS: These findings suggest that fetal exposure to maternal mood dysregulation is associated with a weakened and inflexible salience network. More broadly, they identify maternal mood entropy as a novel marker of early adversity that exhibits long-lasting associations with offspring brain development.

BackgroundFalls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated.MethodsIn this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after one year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy (MRS) after an acute bout of exercise (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS).ResultsAt least one fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400m walk gait speed (1.0 ± 0.2 vs. 1.1 ± 0.2, p