Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.

BACKGROUND: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group. RESULTS: A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug. CONCLUSIONS: Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).

Air Pollution Exposures and Child Executive Function: A U.S. Multi-Cohort Study.

BACKGROUND: Executive function, which develops rapidly in childhood, enables problem solving, focused attention, and planning. Animal models describe executive function decrements associated with ambient air pollution exposure, but epidemiologic studies are limited. METHODS: We examined associations between early childhood air pollution exposure and school-aged executive function in 1,235 children from three U.S. pregnancy cohorts in the ECHO-PATHWAYS Consortium. We derived point-based residential exposures to ambient particulate matter ≤2.5µm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2), and ozone (O3) at ages 0-4 years from spatiotemporal models with a 2-week resolution. We assessed executive function across three domains -- cognitive flexibility, working memory, and inhibitory control -- using performance-based measures and calculated a composite score quantifying overall performance. We fitted linear regressions to assess air pollution - child executive function associations, adjusting for sociodemographic characteristics, maternal mental health, and health behaviors, and examined modification by child sex, maternal education, and neighborhood educational opportunity. RESULTS: In the overall sample, we found hypothesized inverse associations in crude but not adjusted models. Modified associations between NO2 exposure and working memory by neighborhood education opportunity were present (P interaction = 0.05), with inverse associations more pronounced in the "High" and "Very high" categories. Associations of interest did not differ by child sex or maternal education. CONCLUSIONS: This work contributes to the evolving science regarding early-life environmental exposures and child development. There remains a need for continued exploration in future research endeavors, to elucidate the complex interplay between natural environment and social determinants influencing child neurodevelopment.

Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

Can lameness prevalence in dairy herds be predicted from farmers' reports of their motivation to control lameness and barriers to doing so? An observational study from New Zealand.

Understanding what motivates and prevents behavioral change in farmers is a critical step in disease control in dairy cattle. A total of 101 New Zealand dairy farmers across 8 regions were randomly enrolled into a cross-sectional study to investigate farmer barriers and motivators to lameness control for cows managed 100% at pasture and the relationship between these responses and the true lameness status on farm. Trained technicians lameness scored all lactating cows on the enrolled farms on 2 occasions during one lactation. Farm-level prevalence proportions were calculated as the mean of the 2 lameness scores. Enrolled farmers were asked their perception of lameness in the current milking season and responded to 26 ordinal Likert-type items with 5 options ranging from not important at all to extremely important. The questions were grouped under 3 categories; barriers to lameness control (n = 9), impacts of lameness (n = 10), and motivators to control lameness (n = 7). The association between farmer perception of lameness and lameness prevalence was reported using linear regression. Multiple-factor analysis was conducted to identify latent variable themes within the responses. Linear discriminant analysis was used to assess whether barriers, impacts, and motivators could be used to predict farmer perception of lameness and lameness prevalence. Lameness prevalence was 0.8% greater on farms where farmers perceived lameness as a moderate or a major problem compared with farms where the farmer perceived lameness as a minor problem or not a problem. Farmers ranked all potential motivators to lameness control as important and declared few barriers to be important at preventing them from controlling lameness. Feeling sorry for lame cows and pride in a healthy herd were the most important motivators, with lack of time and skilled labor the most important barriers. The most important effects of lameness were cow-related factors such as pain and production, with farm and industry impacts of less importance. Farmers place different weightings of importance on barriers to lameness control compared with motivators for lameness control. The impacts and motivators were strongly correlated with the first dimension from the multiple-factor analysis, with only weak correlation between barriers and the first dimension. Linear discriminant analysis identified that the importance that farmers place on barriers, motivators, and impacts of lameness were poor predictors of farmers' belief in regard to their lameness problem or actual lameness prevalence (above or below the median lameness prevalence for the study cohort). Despite relatively low lameness prevalence, many New Zealand dairy farmers believe lameness is a problem on their farm, and they rank welfare effects of lameness of high importance. To investigate how farmer behavior change can be used to manage lameness, future studies should consider theoretical social science frameworks beyond the theory of planned behavior or involve prospective interventional studies investigating farmer actions instead of beliefs.

Associations between middle childhood executive control aspects and adolescent substance use and externalizing and internalizing problems.

This study examines the degree to which two middle childhood executive control aspects, working memory and combined inhibitory control/flexible shifting, predict adolescent substance use and externalizing and internalizing problems. Participants were 301 children (ages 3-6 years; 48.2% male) recruited from a Midwestern city in the United States and followed into adolescence (ages 14-18 years). Working memory had a statistically significant unadjusted association with externalizing problems (r = -.30, p = .003) in a confirmatory factor analysis. Neither factor significantly predicted any of the adolescent outcomes in a structural equation model that adjusted for each EC aspect, sociodemographic covariates, and middle childhood externalizing and internalizing problems. Stronger prediction of EC aspects might not emerge until they become more fully differentiated later in development.

Farm-level risk factors and treatment protocols for lameness in New Zealand dairy cattle.

AIMS: To identify farm-level risk factors for dairy cow lameness, and to describe lameness treatment protocols used on New Zealand dairy farms. METHODS: One hundred and nineteen farms from eight veterinary clinics within the major dairying regions of New Zealand were randomly enrolled into a cross-sectional lameness prevalence study. Each farmer completed a questionnaire on lameness risk factors and lameness treatment and management. Trained observers lameness scored cattle on two occasions, between October-December (spring, coinciding with peak lactation for most farms) and between January-March (summer, late lactation for most farms). A four-point (0-3) scoring system was used to assess lameness, with animals with a lameness score (LS) ≥2 defined as lame. At each visit, all lactating animals were scored including animals that had previously been identified lame by the farmer. Associations between the farmer-reported risk factors and lameness were determined using mixed logistic regression models in a Bayesian framework, with farm and score event as random effects. RESULTS: A lameness prevalence of 3.5% (2,113/59,631) was reported at the first LS event, and 3.3% (1,861/55,929) at the second LS event. There was a median prevalence of 2.8% (min 0, max 17.0%) from the 119 farms. Most farmers (90/117; 77%) relied on informal identification by farm staff to identify lame animals. On 65% (75/116) of farms, there was no external provider of lame cow treatments, with the farmer carrying out all lame cow treatments. Most farmers had no formal training (69/112; 62%). Animals from farms that used concrete stand-off pads during periods of inclement weather had 1.45 times the odds of lameness compared to animals on farms that did not use concrete stand-off pads (95% equal-tailed credible interval 1.07-1.88). Animals from farms that reported peak lameness incidence from January to June or all year-round, had 0.64 times odds of lameness compared to animals from farms that reported peak lameness incidence from July to December (95% equal-tailed credible interval 0.47-0.88). CONCLUSIONS: Lameness prevalence was low amongst the enrolled farms. Use of concrete stand-off pads and timing of peak lameness incidence were associated with odds of lameness. CLINICAL RELEVANCE: Veterinarians should be encouraging farmers to have formal lameness identification protocols and lameness management plans in place. There is ample opportunity to provide training to farmers for lame cow treatment. Management of cows on stand-off pads should consider the likely impact on lameness.

The prevalence of damaged tails in New Zealand dairy cattle.

AIMS: To undertake a survey of the prevalence of tail deviations, trauma and shortening on a representative selection of New Zealand dairy farms, and to assess whether sampling based on milking order could be used instead of random sampling across the herd to estimate prevalence. METHODS: This was a cross-sectional observational study, with 200 randomly selected farms enrolled across nine regions of New Zealand via selected veterinary practices (one/region). Veterinary clinics enrolled 20-25 farms each depending on region, with 1-2 trained technicians scoring per region. All cows (n = 92,348) present at a milking or pregnancy testing event were tail scored using a modified version of the New Zealand Veterinary Association Industry Scoring System. Palpated lesions were recorded as deviated (i.e. non-linear deformity), shortened (tail shorter than normal) or traumatic (all other lesions). The location of lesions was defined by dividing the tail into three equal zones: upper, middle and lower. A cow could have more than one lesion type and location, and/or multiple lesions of the same type, but for the prevalence calculation, only the presence or absence of a particular lesion was assessed. Prevalence of tail damage calculated using whole herd scoring was compared to random sampling across the herd and sampling from the front and back of the milking order. Bootstrap sampling with replacement was used to generate the sampling distributions across seven sample sizes ranging from 40-435 cows. RESULTS: When scoring all cows, the median prevalence for deviation was 9.5 (min 0.9, max 40.3)%; trauma 0.9 (min 0, max 10.7)%, and shortening was 4.5 (min 1.3, max 10.8)%. Deviation and trauma prevalence varied between regions; the median prevalence of deviations ranged from 6% in the West Coast to 13% in Waikato, and the median prevalence of all tail damage from 7% in the West Coast to 29% in Southland. Sampling based on milking order was less precise than random sampling across the herd. With the latter and using 157 cows, 95% of prevalence estimates were within 5% of the whole herd estimate, but sampling based on milking order needed > 300 cows to achieve the same precision. CONCLUSIONS AND CLINICAL RELEVANCE: The proportion of cows identified as having damaged tails was consistent with recent reports from New Zealand and Ireland, but at 11.5%, the proportion of cows with trauma or deviation is below acceptable standards. An industry-wide programme is needed to reduce the proportion of affected cows.

Exploring the Interaction Between Preschool Executive Control and Caregiver Emotion Socialization in Predicting Adolescent Weight Trajectories.

There is a critical need for research examining how neural vulnerabilities associated with obesity, including lower executive control, interact with family factors to impact weight trajectories across adolescence. Utilizing a longitudinal design, the present study investigated caregivers' emotion socialization practices as a moderator of the association between preschool executive control and adolescent body mass index (BMI) trajectories. Participants were 229 youth (Mage = 5.24, SD = 0.03; 47.2% assigned female at birth; 73.8% White, 3.9% Black, 0.4% Asian American, 21.8% multiracial; 12.7% Hispanic) enrolled in a longitudinal study. At preschool-age, participants completed performance-based executive control tasks, and their caregivers reported on their typical emotion-related socialization behaviors (i.e., supportive and nonsupportive responses to children's negative emotions). Participants returned for annual laboratory visits at ages 14 through 17, during which their height and weight were measured to calculate BMI. Although neither preschool executive control nor caregiver emotion-related socialization behaviors were directly associated with BMI growth in adolescence, supportive responses moderated the association between executive control and BMI trajectories. The expected negative association between lower preschool executive control and greater BMI growth was present at below average levels of supportive responses, suggesting that external regulation afforded by supportive responses might reduce risk for adolescent overweight and obesity among children with lower internal self-regulatory resources during preschool. Findings highlight the importance of efforts to bolster executive control early in development and targeted interventions to promote effective caregiver emotion socialization (i.e., more supportive responses) for youth with lower internal self-regulatory abilities to mitigate risk for overweight and obesity and promote health across childhood and adolescence.

Lineage tracing and analog recording in mammalian cells by single-site DNA writing.

Studying cellular and developmental processes in complex multicellular organisms can require the non-destructive observation of thousands to billions of cells deep within an animal. DNA recorders address the staggering difficulty of this task by converting transient cellular experiences into mutations at defined genomic sites that can be sequenced later in high throughput. However, existing recorders act primarily by erasing DNA. This is problematic because, in the limit of progressive erasure, no record remains. We present a DNA recorder called CHYRON (Cell History Recording by Ordered Insertion) that acts primarily by writing new DNA through the repeated insertion of random nucleotides at a single locus in temporal order. To achieve in vivo DNA writing, CHYRON combines Cas9, a homing guide RNA and the template-independent DNA polymerase terminal deoxynucleotidyl transferase. We successfully applied CHYRON as an evolving lineage tracer and as a recorder of user-selected cellular stimuli.

Placental transcriptomic signatures of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05. RESULTS: In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function. CONCLUSION: This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Does preschool executive control mediate the impact of early environmental unpredictability and deprivation on the general factor of psychopathology a decade later?

BACKGROUND: Although deprivation has been consistently shown to increase risk for psychopathology through impaired executive control, the unique effects of other dimensions of early adversity, such as unpredictability, on executive control development are poorly understood. The current study evaluated whether deprivation and/or unpredictability early in life have unique effects on the general factor of psychopathology through impaired preschool executive control. METHODS: Participants included 312 children (51% female) oversampled for greater sociodemographic risk. Preschool executive control was measured using a battery of nine developmentally appropriate executive control tasks. Dimensions of adversity were measured with observational and caregiver assessments, and psychopathology was measured with caregiver and child reports. RESULTS: In separate models, both deprivation and unpredictability had significant indirect effects on the adolescent general factor of psychopathology through impaired preschool executive control. However, when both dimensions of adversity were included simultaneously, early life deprivation, but not unpredictability, was uniquely associated with the general factor of psychopathology in adolescence through impaired preschool executive control. CONCLUSIONS: Preschool executive control appears to be a transdiagnostic mechanism through which deprivation, but not unpredictability, increases risk for the general factor of psychopathology in adolescence. Results elucidate potential transdiagnostic targets for intervention efforts aimed at reducing the development and maintenance of psychopathology across the life span.

Chasing the fitness optimum: temporal variation in the genetic and environmental expression of life-history traits for a perennial plant.

BACKGROUND AND AIMS: The ability of plants to track shifting fitness optima is crucial within the context of global change, where increasing environmental extremes may have dramatic consequences for life history, fitness, and ultimately population persistence. However, tracking changing conditions relies on the relationship between genetic and environmental variance, where selection may favour plasticity, the evolution of genetic differences, or both depending on the spatial and temporal scale of environmental heterogeneity. METHODS: Over three years, we compared the genetic and environmental components of phenological and life-history variation in a common environment for the spring perennial Geum triflorum. Populations were sourced from alvar habitats that exhibit extreme but predictable annual flood-desiccation cycles and prairie habitats that exhibit similar but less predictable variation in water availability. KEY RESULTS: Heritability was generally higher for early life-history (emergence probability) relative to later life-history traits (total seed mass), indicating that traits associated with establishment are under stronger genetic control relative to later life-history fitness expressions, where plasticity may play a larger role. This pattern was particularly notable in seeds sourced from environmentally extreme but predictable alvar habitats relative to less predictable prairie environments. Fitness landscapes based on seed source origin, largely characterized by varying water availability and flower production, described selection as the degree of maladaptation of seed source environment relative to the prairie common garden environment. Plants from alvar populations were consistently closer to the fitness optimum across all years. Annually, the breadth of the fitness optimum expanded primarily along a moisture gradient, with inclusion of more populations onto the expanding optimum. CONCLUSIONS: These results highlight the importance of temporally and spatially varying selection in life-history evolution, indicating plasticity may become a primary mechanism needed to track fitness for later life-history events within perennial systems.

Bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes in adults: A 24-week, randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the relative safety and effectiveness of bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes mellitus. METHODS: In total, 317 participants were randomized to receive bexagliflozin or placebo plus metformin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24, with secondary endpoints for systolic blood pressure (SBP), fasting plasma glucose and weight loss. An open label arm enrolled participants with HbA1c >10.5% and was analysed separately. RESULTS: The mean change in HbA1c was -1.09% (95% CI -1.24%, -0.94%) in the bexagliflozin arm and -0.56% (-0.71%, -0.41%) in the placebo arm, a difference of -0.53% (-0.74%, -0.32%; p < .0001). Excluding observations after rescue medication, the intergroup difference was -0.70% (-0.92, -0.48; p < .0001). The open label group change in HbA1c was -2.82% (-3.23%, -2.41%). Placebo-adjusted changes from baseline SBP, fasting plasma glucose and body mass were -7.07 mmHg (-9.83, -4.32; p < .0001), -1.35 mmol/L (-1.83, -0.86; p < .0001) and -2.51 kg (-3.45, -1.57; p < .0001). Adverse events affected 42.4% and 47.2% of subjects in the bexagliflozin and placebo arms, respectively; fewer subjects in the bexagliflozin arm experienced serious adverse events. CONCLUSIONS: Bexagliflozin produced clinically meaningful improvement in glycaemic control, estimated glomerular filtration rate and SBP when added to metformin in a population of adults with diabetes.

A 96-week, double-blind, randomized controlled trial comparing bexagliflozin to glimepiride as an adjunct to metformin for the treatment of type 2 diabetes in adults.

AIM: To compare the effects of bexagliflozin tablets 20 mg, with those of optimally titrated glimepiride when used to treat adults with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin. METHODS: Adults with type 2 diabetes (n = 426) taking metformin, and with a glycated haemoglobin (HbA1c) level between 53 and 91 mmol/mol [7.0% and 10.5%], were randomized to receive bexagliflozin tablets 20 mg or titrated glimepiride. The primary endpoint was the intergroup difference in the change from baseline to Week 60 in percent HbA1c. Secondary endpoints included changes from baseline in body mass and systolic blood pressure (SBP), and proportion of subjects experiencing severe or documented symptomatic hypoglycaemia. RESULTS: The intergroup difference in percent HbA1c (bexagliflozin minus glimepiride) from baseline to Week 60 was -0.55 mmol/mol (95% confidence interval [CI] -2.30, 1.20)-[-0.05% (-0.21, 0.11)], establishing noninferiority of bexagliflozin to glimepiride by the prespecified margin of 3.83 mmol/mol [0.35%]. Prespecified tests gave, in order, a difference in body mass of -4.31 kg (95% CI -5.10, -3.52; P < 0.0001), a difference in SBP of -6.53 mm Hg (95% CI -10.56, -2.51; P = 0.0008), and an odds ratio of 0.12 (95% CI 0.05, 0.28; P < 0.0001) for severe or documented symptomatic hypoglycaemia. At the follow-up visit the mean difference in estimated glomerular filtration rate (eGFR) between arms was 6.05 mL min-1 per 1.73 m2 (95% CI, 3.24, 8.87; P < 0.0001). CONCLUSIONS: Bexagliflozin was noninferior to glimepiride in lowering HbA1c, was superior to glimepiride for decreases in body mass and SBP, and was associated with significantly fewer hypoglycaemic events than glimepiride. A favourable effect on eGFR was observed.

Preschool Executive Control, Temperament, and Adolescent Dietary Behaviors.

BACKGROUND: Child temperament styles characterized by increased emotionality or pleasure seeking may increase risk for less healthful eating patterns, while strong executive control (EC) may be protective. The interaction of these characteristics with longitudinal outcomes has not yet been examined. PURPOSE: The aim of this study was to examine the association of preschool temperament and EC, as well as their interaction with adolescent eating. METHODS: Preschoolers (N = 313) were recruited into a longitudinal study, with behavioral measurement of EC at age 5.25 years, temperament assessed multiple times across preschool, and eating outcomes assessed in adolescence (mean age = 15.34 years). RESULTS: Separate latent moderated structural equation models demonstrated that weaker EC was associated with eating less healthful foods, including high sugar foods, sugar-sweetened beverages (SSBs), and convenience foods (p < .05). In the moderation models, negative affectivity temperament was correlated with eating less healthful foods, high sugar foods, and SSBs (p < .05). Children lower in surgency/extraversion temperament were more likely to drink SSBs. There was an interaction between temperament and EC, such that children high in negative affectivity with weaker EC were particularly more likely to consume less healthful foods, high sugar foods, and SSBs (p < .05). There was no interaction of surgency with EC and food consumption. CONCLUSIONS: Child characteristics measured early in development were associated with later adolescent eating behaviors. Adequate EC could be necessary to counteract the drive toward eating associated with temperaments high in negative affectivity.

A preschool temperament style called Negative Affectivity, characterized by high levels of reactivity and negative emotion, predicted eating patterns a decade later. These children were more likely to eat less healthful foods and drink sugary drinks as adolescents. Strong executive function skills were important for redirecting toward healthful eating in children with Negative Affectivity.

Association of Gestational Diabetes Mellitus and Perinatal Maternal Depression with Early Childhood Behavioral Problems: An Environmental Influences on Child Health Outcomes (ECHO) Study.

This study examined the association of gestational diabetes mellitus (GDM), prenatal, and postnatal maternal depressive symptoms with externalizing, internalizing, and autism spectrum problems on the Preschool Child Behavior Checklist in 2379 children aged 4.12 ± 0.60 (48% female; 47% White, 32% Black, 15% Mixed Race, 4% Asian, <2% American Indian/Alaskan Native, <2% Native Hawaiian; 23% Hispanic). Data were collected from the NIH Environmental influences on Child Health Outcomes (ECHO) Program from 2009-2021. GDM, prenatal, and postnatal maternal depressive symptoms were each associated with increased child externalizing and internalizing problems. GDM was associated with increased autism behaviors only among children exposed to perinatal maternal depressive symptoms above the median level. Stratified analyses revealed a relation between GDM and child outcomes in males only.

Intergenerational transmission of stress: Multi-domain stressors from maternal childhood and pregnancy predict children's mental health in a racially and socioeconomically diverse, multi-site cohort.

PURPOSE: Despite growing recognition that unfortunately common maternal stress exposures in childhood and pregnancy may have intergenerational impacts on children's psychiatric health, studies rarely take a life course approach. With child psychopathology on the rise, the identification of modifiable risk factors is needed to promote maternal and child well-being. In this study, we examined associations of maternal exposure to childhood traumatic events (CTE) and pregnancy stressful life events (PSLE) with child mental health problems in a large, sociodemographically diverse sample. METHODS: Participants were mother-child dyads in the ECHO-PATHWAYS consortium's harmonized data across three U.S. pregnancy cohorts. Women completed questionnaires regarding their own exposure to CTE and PSLE, and their 4-6-year-old child's mental health problems using the Child Behavior Checklist (CBCL). Regression analyses estimated associations between stressors and child total behavior problems, adjusting for confounders. RESULTS: Among 1948 dyads (child age M = 5.13 (SD = 1.02) years; 38% Black, 44% White; 8.5% Hispanic), maternal history of CTE and PSLE were independently associated with children's psychopathology: higher CTE and PSLE counts were related to higher total problems ([ßCTE = 0.11, 95% CI [.06, .16]; ßSLE = 0.21, 95% CI [.14, 0.27]) and greater odds of clinical levels of problems (ORCTE = 1.41; 95% CI [1.12, 1.78]; ORPSLE = 1.36; 95% CI [1.23, 1.51]). Tests of interaction showed PSLEs were more strongly associated with child problems for each additional CTE experienced. CONCLUSION: Findings confirm that maternal exposure to CTE and PSLE are independently associated with child mental health, and history of CTE exacerbates the risk associated with PSLE, highlighting intergenerational risk pathways for early psychopathology. Given the prevalence of these exposures, prevention and intervention programs that reduce childhood trauma and stress during pregnancy will likely positively impact women's and their children's health.

Randomized, noninferiority trial evaluating the efficacy of a novel teat sealant in pasture grazed dairy cows.

The intramammary infusion at the end of lactation of a bismuth subnitrate internal teat sealant (ITS), with no antibiotic component has been shown to be an effective means of reducing new intramammary infections over the dry period. There has, however, been very few comparative studies between different brands of ITS under grazed pasture conditions. The objectives of this study were, therefore, to determine if a new bismuth subnitrate internal teal sealant (ShutOut, MSD Animal Health) was noninferior to Teatseal (Zoetis) regarding end-points such as (a) detection of the ITS product after calving, (b) clinical mastitis during the dry period and early lactation, and (c) subclinical mastitis at 30 to 60 d in milk. A total of 1,105 mixed-age cattle were enrolled across 2 farms comparing 2 ITS products for detection of the ITS at calving and prevention of clinical and subclinical mastitis. Both ITS contained 65% (2.6 g) bismuth salts emulsified in ≤ 1.4 g of mineral oil (ShutOut as investigational product, IVP; Teatseal as control product, CPT). At dry-off, treatment was allocated to every second cow. All cows met industry best practice criteria for using ITS treatment without antibiotics. Outcomes included detection of ITS at first stripping of the udder by the farmer, clinical mastitis (CM) from dry-off to 30 d following calving and subclinical mastitis at 30 to 60 d following calving. For ITS detection, a generalized mixed linear regression model was used to model the data, with clustering of quarters within cow accounted for by including cow as a random intercept. Clinical mastitis was analyzed at the cow-level using a Fisher's exact test, and SCC was modeled using a negative binomial distribution. The IVP was noninferior to the CPT for ITS detection following calving. There were 1344/1800 (71.5%) of quarters with ITS detection in the IVP in comparison to 1076/1604 (67.1%) of quarters in the CPT treated group. The quarter-level CM incidence risk was low (45 cases out 4,324 quarters; 1.04%). The overall cow-level CM risk was 4.1% (44/1081), with 20/540 (3.7%) cases in animals in the IVP group and 24/541 (4.4%) cases in animals in the CPT group. The IVP was noninferior to the CPT for cow-level mastitis incidence. The median SCC for all animals was 23,000 cells/mL, with a mean of 92,000 cells/mL. The back-transformed estimated marginal mean estimated SCC was 84,800 (95% CI 75,200-95,600) cells/mL for animals in the IVP group, and 98,800 (95% CI 87,600-111,300) cells/mL for animals in the CPT group. The IVP was, therefore, noninferior for all outcomes measured.

Social Network Analysis of Diffusion Among American Indian Youth in a Culturally Adapted, Family-focused Prevention Program.

Diffusion can contribute to the spread of preventive intervention effects from participants to non-participants, but best practices for randomized trials prevent contamination of conditions. These practices conflict with cultural values of community benefit, which are salient among American Indians. This study embedded social network measures within a randomized trial of the Bii-Zin-Da-De-Dah (BZDDD) family-focused prevention program to characterize youth's social networks, describe the nature and content of sharing, and test for diffusion effects on cultural engagement (ethnic identification, cultural socialization, cultural practices) and substance use. Participants were 256 American Indian youths enrolled in the trial who provided self-reports of their social networks and indicated whether specific program content was shared with or received from others, while completing cultural engagement and substance use questionnaires across three waves. Results indicated that social networks were comprised mainly of peers and same-age family members (e.g., cousins). Program sharing was not uncommon. For example, 51% of responding intervention youth reported talking with non-participants about BZDDD at wave 2, typically (53%) with similar-age friends and family who were, most often (71%), out of the home. Evidence for diffusion effects was limited, but did indicate that control youth who had some exposure to BZDDD had a significantly higher average cultural/ethnic identity scale score at wave 2 and were more likely to ask an elder for advice than control youth who had no BZDDD exposure in adjusted analyses. Findings illustrate the value of measuring and testing for potential effects of diffusion in prevention trials with American Indians.

Early executive control buffers risk for adolescent psychopathology during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a global impact on youth mental health, and there is a critical need for research examining individual factors that contribute to increased psychopathology during the pandemic. The current study explored whether executive control (EC) abilities in early childhood interact with COVID-related stress to attenuate risk for adolescent psychopathology during the first 6 months of the pandemic. METHODS: Participants were 337 youth (49% female) living in a small midwestern city in the United States. Participants completed EC tasks when they were approximately 4.5 years old as part of a longitudinal study investigating cognitive development. At annual laboratory visits during adolescence and before the pandemic, participants (Mage = 14.57) reported on mental health symptoms. In July and August of 2020, participants (Mage = 16.57) reported on COVID-related stress and depression, anxiety, and trauma symptoms. RESULTS: COVID-related stress was associated with increased internalizing problems after controlling for prepandemic symptom levels. Further, the impact of COVID-related stress on adolescent internalizing problems was moderated by preschool EC, with higher levels of EC buffering the effects of COVID-related stress on adolescent internalizing problems. CONCLUSIONS: Findings highlight the importance of promoting EC early in development, as well as screening for EC deficits and implementing targeted intervention strategies across the lifespan to help reduce the impact of stress on adolescent internalizing problems.