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Background and Objectives: Noradrenergic dysregulation is important in the pathophysiology of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD); pharmacotherapies targeting adrenergic function have potential as treatment for comorbidity. Dexmedetomidine (sublingual film formulation—BXCL501; IGALMI) is a highly potent, selective ⍺2‐adrenergic receptor agonist and may be superior to other pharmacotherapeutic approaches. A within subjects, phase 1b safety laboratory study was conducted to evaluate adverse effects of BXCL501 when combined with alcohol; BXCL501's potential efficacy was also explored. Methods: Heavy drinker participants with a diagnosis of or who were at risk for PTSD participated in three separate test days which included pretreatment with BXCL501 (40 µg, 80 µg or placebo) administered in a randomized, double‐blind fashion, followed by three testing conditions: alcohol cue reactivity, trauma‐induced reactivity, and IV ethanol administration. Safety outcomes included blood pressure (BP) and sedation. Exploratory outcomes included alcohol craving, trauma‐induced anxiety and craving and subjective effects of alcohol. Results: Ten of twelve randomized participants competed the entire study. BXCL501 (80 µg) was associated with expected mild changes in BP and sedation; administration with alcohol did not affect those parameters. There were no clinically significant adverse effects. BXCL501 attenuated trauma‐induced anxiety and attenuated subjective effects of alcohol. Discussions and Conclusions: BXCL501 is safe for use in humans who may drink alcohol while undergoing treatment. BXCL501 may be explored as a potential treatment for PTSD and AUD. Scientific Significance: This is the first study to provide scientific support for BXCL501's potential to treat PTSD and comorbid AUD. Answer questions and earn CME credit [ABSTRACT FROM AUTHOR]

Objectives. To determine whether the Communities That HEAL (CTH) intervention is effective in increasing naloxone distribution compared with usual care. Methods. The HEALing (Helping to End Addiction Long-Term) Communities Study (HCS) is a cluster-randomized, parallel-arm, wait-list controlled implementation science trial testing the impact of the CTH intervention on increasing the use of evidence-based practices to lower opioid-related overdose deaths. Communities (n = 67) highly impacted by opioid overdose in Kentucky, Massachusetts, New York, and Ohio were allocated to CTH intervention (n = 34) or wait-list comparison (usual care; n = 33) arms. The primary outcome for this study was the number of naloxone units distributed in HCS communities during the comparison period (July 1, 2021‒June 30, 2022), examined using an intent-to-treat negative binomial regression model. Results. Naloxone distribution was 79% higher in the CTH intervention versus usual care arm (adjusted relative rate = 1.79; 95% confidence interval = 1.28, 2.51; P =.001; adjusted rates of naloxone distribution 3378 vs 1884 naloxone units per 100 000 residents), when controlling for urban‒rural status, state, baseline opioid-related overdose death rate, and baseline naloxone distribution rate. Conclusions. The CTH intervention increased naloxone distribution compared with usual care in communities highly impacted by the opioid crisis. Trial Registration. ClinicalTrials.gov identifier: NCT04111939. (Am J Public Health. 2025;115(1):83–94. https://doi.org/10.2105/AJPH.2024.307845) [ABSTRACT FROM AUTHOR]

Accurate HIV-1 incidence estimation is critical to the success of HIV-1 prevention strategies. Current assays are limited by high false recent rates (FRRs) in certain populations and a short mean duration of recent infection (MDRI). Dynamic early HIV-1 antibody response kinetics were harnessed to identify biomarkers for improved incidence assays. We conducted retrospective analyses on circulating antibodies from known recent and longstanding infections and evaluated binding and avidity measurements of Env and non-Env antigens and multiple antibody forms (i.e., IgG, IgA, IgG3, IgG4, dIgA, and IgM) in a diverse panel of 164 HIV-1-infected participants (clades A, B, C). Discriminant function analysis identified an optimal set of measurements that were subsequently evaluated in a 324-specimen blinded biomarker validation panel. These biomarkers included clade C gp140 IgG3, transmitted/founder clade C gp140 IgG4 avidity, clade B gp140 IgG4 avidity, and gp41 immunodominant region IgG avidity. MDRI was estimated at 215 day or alternatively, 267 days. FRRs in untreated and treated subjects were 5.0% and 3.6%, respectively. Thus, computational analysis of dynamic HIV-1 antibody isotype and antigen interactions during infection enabled design of a promising HIV-1 recency assay for improved cross-sectional incidence estimation.

Human cytomegalovirus (HCMV) is the most common congenital infection and a known cause of microcephaly, sensorineural hearing loss, and cognitive impairment among newborns worldwide. Natural maternal HCMV immunity reduces the incidence of congenital infection, but does not prevent the disease altogether. We employed a nonhuman primate model of congenital CMV infection to investigate the ability of preexisting antibodies to protect against placental CMV transmission in the setting of primary maternal infection and subsequent viremia, which is required for placental virus exposure. Pregnant, CD4+ T cell-depleted, rhesus CMV-seronegative (RhCMV-seronegative) rhesus monkeys were treated with either standardly produced hyperimmune globulin (HIG) from RhCMV-seropositive macaques or dose-optimized, potently RhCMV-neutralizing HIG prior to intravenous challenge with an RhCMV mixture. HIG passive infusion provided complete protection against fetal loss in both groups. The dose-optimized, RhCMV-neutralizing HIG additionally inhibited placental transmission of RhCMV and reduced viral replication and diversity. Our findings suggest that the presence of durable and potently neutralizing antibodies at the time of primary infection can prevent transmission of systemically replicating maternal RhCMV to the developing fetus, and therefore should be a primary target of vaccines to eliminate this neonatal infection.

Background: Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ‐opioid antagonist and a partial agonist of mu (μ) opioid receptors. Whereas naltrexone blocks all μ‐mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ‐opioid receptor antagonist it available for clinical use, we tested this combination in a proof‐of‐concept study. Methods: Consenting participants were enrolled in a Phase II, multisite, double‐blind, randomized, placebo‐controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended‐release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n = 75) were randomized (1:1:1) to receive either buprenorphine 2 mg/day plus naltrexone‐XR (n = 35), buprenorphine 8 mg/day plus naltrexone‐XR (n = 6) or SL plus injectable placebo (n = 34) for 12 weeks. The buprenorphine 8 mg/day plus naltrexone‐XR arm was dropped early in the trial due to the negative impact of COVID‐19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician‐Administered PTSD Scale (CAPS‐5) and a reduction of ≥1 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow‐Back. Results: Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone‐XR and placebo group for the primary composite outcome (OR = 0.63; p‐value = 0.52), or the subcomponents of the PTSD outcome (OR = 0.76; p‐value = 0.69) and AUD outcome (OR = 0.17; p‐value = 0.08). The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk level reduction than the buprenorphine plus naltrexone‐XR arm (OR = 0.18, p value = 0.02). Conclusions: This is the first study to evaluate the potential of κ‐opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone‐XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures. [ABSTRACT FROM AUTHOR]

This study examined gender differences in the level and developmental course of relational aggression in middle childhood, as well as early predictors and outcomes of relational aggression, after controlling for concurrent physical aggression. Relational (RAgg) and Physical aggression (PAgg) scores for 558 boys and 545 girls at the ages of eight to 11 in the NICHD Study of Early Child Care and Youth Development (SECCYD) were created by combining the highest rating for each item across mother and teacher reports. Longitudinal analyses were conducted using latent curve models of RAgg with PAgg as a time-varying covariate, with all parameters allowed to vary by gender. Boys and girls had different growth parameters of RAgg. Girls' RAgg intercept was higher, and the slope was not different from zero; boys' RAgg intercept was lower, and the slope declined. Mother-child conflict in early childhood predicted RAgg intercept for both boys and girls, but maternal harsh control and sensitivity were also uniquely predictive for girls whereas center care was uniquely predictive for boys. RAgg intercept predicted adolescent self-reports of depression for girls and delinquency and risk-taking for both boys and girls; the magnitude of the association with risk taking was significantly greater for boys.

We evaluated the psychometric properties of the Responses to Stress Questionnaire (RSQ; Connor-Smith, Compas, Saltzman, Thomsen, & Wadsworth, 2000) in a sample of Bosnian youth (N = 665; age = 15 to 20 years) five years post-war. Participants reported on their coping and involuntary responses to post-war stressors including trauma reminders, loss reminders, and family conflict. Confirmatory factor analysis supported a four-factor model comprised of primary control engagement coping, secondary control engagement coping, disengagement coping, and involuntary stress responses. Results support the reliability and validity of the RSQ to adolescents growing up in stressful post-war contexts. (Contains 3 figures and 7 tables.)

Over the past five decades, the federal government and most states have invested heavily in providing publicly-funded child care and early education opportunities for 3- and 4-year-old children from low-income families. Policy makers and parents want to identify "the level" or "threshold" in quality of teacher-child interaction and intentional instruction related to better child outcomes to most efficiently use child care to improve school readiness. Academic and social outcomes for children from low-income families were predicted from measures of teacher-child interactions and instructional quality in a spline regression analysis of data from an 11-state pre-kindergarten evaluation. Findings suggested that the quality of teacher-child interactions was a stronger predictor of higher social competence and lower levels of behavior problems in higher than in lower quality classrooms. Further, findings suggested that quality of instruction was related to language, read and math skills more strongly in higher quality than in lower quality classrooms. These findings suggest that high-quality classrooms may be necessary to improve social and academic outcomes in pre-kindergarten programs for low-income children. (Contains 2 figures and 3 tables.)

This nonexperimental, longitudinal field study examines the extent to which variation in observed classroom supports (quality of emotional and instructional interactions and amount of exposure to literacy and math activities) predicts trajectories of achievement in reading and math from 54 months to fifth grade. Growth mixture modeling detected two latent classes of readers: fast readers whose skills developed rapidly and leveled off, and a typical group for which reading growth was somewhat less rapid. Only one latent class was identified for math achievement. For reading, there were small positive associations between observed emotional quality of teacher-child interactions and growth. Growth in math achievement showed small positive relations with observed emotional interactions and exposure to math activities. There was a significant interaction between quality and quantity of instruction for reading such that at higher levels of emotional quality there was less of a negative association between amount of literacy exposure and reading growth. (Contains 5 tables, 4 figures, and 1 note.)

This study introduces a novel application of structural equation modeling (SEM) for the analysis of cortisol data that are collected using a pre-post-post design. By way of an extended example, an SEM model is developed that permits an examination of both the overall level of cortisol, as well as changes in cortisol (reactivity and regulation), as predictors of cognitive (executive) and behavioral functioning in 3- to 5-year-old children (N = 171) attending Head Start. The SEM model makes use of the parameterization of latent curve models. Throughout the extended example, the strengths of using an SEM approach for the analysis of cortisol data that are collected using pre-post-post designs is highlighted.

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1467-8624.2010.01431.x Byline: Deborah Lowe Vandell (1), Jay Belsky (2), Margaret Burchinal (3), Laurence Steinberg (4), Nathan Vandergrift (5) Abstract: Relations between nonrelative child care (birth to 41/2 years) and functioning at age 15 were examined (N = 1,364). Both quality and quantity of child care were linked to adolescent functioning. Effects were similar in size as those observed at younger ages. Higher quality care predicted higher cognitive-academic achievement at age 15, with escalating positive effects at higher levels of quality. The association between quality and achievement was mediated, in part, by earlier child-care effects on achievement. High-quality early child care also predicted youth reports of less externalizing behavior. More hours of nonrelative care predicted greater risk taking and impulsivity at age 15, relations that were partially mediated by earlier child-care effects on externalizing behaviors. Author Affiliation: (1)University of California, Irvine (2)Birkbeck University of London (3)University of California, Irvine (4)Temple University (5)Duke University (6) Article note: Correspondence concerning this article should be addressed to Deborah Lowe Vandell, Department of Education, University of California, 3200 Education Building, Irvine, CA 92697. Electronic mail may be sent to dvandell@uci.edu.

Background: The HEALing (Helping to End Addiction Long-termSM) Communities Study (HCS) is a multi-site parallel group cluster randomized wait-list comparison trial designed to evaluate the effect of the Communities That Heal (CTH) intervention compared to usual care on opioid overdose deaths. Covariate-constrained randomization (CCR) was applied to balance the community-level baseline covariates in the HCS. The purpose of this paper is to evaluate the performance of model-based tests and permutation tests in the HCS setting. We conducted a simulation study to evaluate type I error rates and power for model-based and permutation tests for the multi-site HCS as well as for a subgroup analysis of a single state (Massachusetts). We also investigated whether the maximum degree of imbalance in the CCR design has an impact on the performance of the tests.Methods: The primary outcome, the number of opioid overdose deaths, is count data assessed at the community level that will be analyzed using a negative binomial regression model. We conducted a simulation study to evaluate the type I error rates and power for 3 tests: (1) Wald-type t-test with small-sample corrected empirical standard error estimates, (2) Wald-type z-test with model-based standard error estimates, and (3) permutation test with test statistics calculated by the difference in average residuals for the two groups.Results: Our simulation results demonstrated that Wald-type t-tests with small-sample corrected empirical standard error estimates from the negative binomial regression model maintained proper type I error. Wald-type z-tests with model-based standard error estimates were anti-conservative. Permutation tests preserved type I error rates if the constrained space was not too small. For all tests, the power was high to detect the hypothesized 40% reduction in opioid overdose deaths for the intervention vs. comparison group both for the overall HCS and the subgroup analysis of Massachusetts (MA).Conclusions: Based on the results of our simulation study, the Wald-type t-test with small-sample corrected empirical standard error estimates from a negative binomial regression model is a valid and appropriate approach for analyzing cluster-level count data from the HEALing Communities Study.Trial Registration: ClinicalTrials.gov http://www.Clinicaltrials: gov ; Identifier: NCT04111939. [ABSTRACT FROM AUTHOR]

Abstract Background Breastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected. As a genetic bottleneck severely restricts the number of postnatally-transmitted variants, genetic or phenotypic properties of the virus Envelope (Env) could be important for the establishment of infant infection. We examined the efficiency of virologic functions required for initiation of infection in the gastrointestinal tract and the neutralization sensitivity of HIV-1 Env variants isolated from milk of three postnatally-transmitting mothers (n=13 viruses), five clinically-matched nontransmitting mothers (n=16 viruses), and seven postnatally-infected infants (n = 7 postnatally-transmitted/founder (T/F) viruses). Results There was no difference in the efficiency of epithelial cell interactions between Env virus variants from the breast milk of transmitting and nontransmitting mothers. Moreover, there was similar efficiency of DC-mediated trans-infection, CCR5-usage, target cell fusion, and infectivity between HIV-1 Env-pseudoviruses from nontransmitting mothers and postnatal T/F viruses. Milk Env-pseudoviruses were generally sensitive to neutralization by autologous maternal plasma and resistant to breast milk neutralization. Infant T/F Env-pseudoviruses were equally sensitive to neutralization by broadly-neutralizing monoclonal and polyclonal antibodies as compared to nontransmitted breast milk Env variants. Conclusion Postnatally-T/F Env variants do not appear to possess a superior ability to interact with and cross a mucosal barrier or an exceptional resistance to neutralization that define their capability to initiate infection across the infant gastrointestinal tract in the setting of preexisting maternal antibodies.