Associations between DNA methylation age acceleration, depressive symptoms, and cardiometabolic traits in African American mothers from the InterGEN study

Background : African American women (AAW) have a high risk of both cardiometabolic (CM) illness and depressive symptoms. Depressive symptoms co-occur in individuals with CM illness at higher rates than the general population, and accelerated aging may explain this. In this secondary analysis, we examined associations between age acceleration; depressive symptoms; and CM traits (hypertension, diabetes mellitus [DM], and obesity) in a cohort of AAW. Methods : Genomic and clinical data from the InterGEN cohort (n = 227) were used. Age acceleration was based on the Horvath method of DNA methylation (DNAm) age estimation. Accordingly, DNAm age acceleration (DNAm AA) was defined as the residuals from a linear regression of DNAm age on chronological age. Spearman’s correlations, linear and logistic regression examined associations between DNAm AA, depressive symptoms, and CM traits. Results : DNAm AA did not associate with total depressive symptom scores. DNAm AA correlated with specific symptoms including selfdisgust/ self-hate (−0.13, 95% CI −0.26, −0.01); difficulty with making decisions (−0.15, 95% CI −0.28, −0.02); and worry over physical health (0.15, 95% CI 0.02, 0.28), but were not statistically significant after multiple comparison correction. DNAm AA associated with obesity (0.08, 95% CI 1.02, 1.16), hypertension (0.08, 95% CI 1.01, 1.17), and DM (0.20, 95% CI 1.09, 1.40), after adjustment for potential confounders. Conclusions : Associations between age acceleration and depressive symptoms may be highly nuanced and dependent on study design contexts. Factors other than age acceleration may explain the connection between depressive symptoms and CM traits. AAW with CM traits may be at increased risk of accelerated aging.The InterGEN study was funded by the National Institute of Nursing Research of the National Institutes of Health (R01NR013520).https://journals.sagepub.com/home/gaeam2023Psycholog

The GJ 436 System: Directly Determined Astrophysical Parameters of an M-Dwarf and Implications for the Transiting Hot Neptune

The late-type dwarf GJ 436 is known to host a transiting Neptune-mass planet in a 2.6-day orbit. We present results of our interferometric measurements to directly determine the stellar diameter ($R_{\star} = 0.455 \pm 0.018 R_{\odot}$) and effective temperature ($T_{\rm EFF} = 3416 \pm 54$ K). We combine our stellar parameters with literature time-series data, which allows us to calculate physical and orbital system parameters, including GJ 436's stellar mass ($M_{\star} = 0.507^{+ 0.071}_{- 0.062} M_{\odot}$) and density ($\rho_* = 5.37^{+ 0.30}_{- 0.27} \rho_\odot$), planetary radius ($R_{p} = 0.369^{+ 0.015}_{- 0.015} R_{Jupiter}$), planetary mass ($M_{p} = 0.078^{+ 0.007}_{- 0.008} M_{Jupiter}$), implying a mean planetary density of $\rho_{p} = 1.55^{+ 0.12}_{- 0.10} \rho_{Jupiter}$. These values are generally in good agreement with previous literature estimates based on assumed stellar mass and photometric light curve fitting. Finally, we examine the expected phase curves of the hot Neptune GJ 436b, based on various assumptions concerning the efficiency of energy redistribution in the planetary atmosphere, and find that it could be constrained with {\it Spitzer} monitoring observations.Comment: 10 pages, 4 tables, 9 figures; accepted for publication in ApJ; incorporated referee's comments and associated change

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Sexual dimorphism of volume reduction but not cognitive deficit in fetal alcohol spectrum disorders: A combined diffusion tensor imaging, cortical thickness and brain volume study

Quantitative magnetic resonance imaging (MRI) has revealed abnormalities in brain volumes, cortical thickness and white matter microstructure in fetal alcohol spectrum disorders (FASD); however, no study has reported all three measures within the same cohort to assess the relative magnitude of deficits, and few studies have examined sex differences. Participants with FASD (n=70; 30 females; 5–32years) and healthy controls (n=74; 35 females; 5–32years) underwent cognitive testing and MRI to assess cortical thickness, regional brain volumes and fractional anisotropy (FA)/mean diffusivity (MD) of white matter tracts. A significant effect of group, age-by-group, or sex-by-group was found for 9/9 volumes, 7/39 cortical thickness regions, 3/9 white matter tracts, and 9/10 cognitive tests, indicating group differences that in some cases differ by age or sex. Volume reductions for several structures were larger in males than females, despite similar deficits of cognition in both sexes. Correlations between brain structure and cognitive scores were found in females of both groups, but were notably absent in males. Correlations within a given MRI modality (e.g. total brain volume and caudate volume) were prevalent in both the control and FASD groups, and were more numerous than correlations between measurement types (e.g. volumes and diffusion tensor imaging) in either cohort. This multi-modal MRI study finds widespread differences of brain structure in participants with prenatal alcohol exposure, and to a greater extent in males than females which may suggest attenuation of the expected process of sexual dimorphism of brain structure during typical development. Keywords: Gender, Prenatal alcohol exposure, Diffusion tensor imaging, Cortical thickness, Brain volume, Cognitio

A 79-kb paternally inherited 7q32.2 microdeletion involving MEST in a patient with a Silver-Russell syndrome-like phenotype

Maternal uniparental disomy of human chromosome 7 [upd(7)mat] is well-characterized as a cause of the growth disorder Silver-Russell syndrome (SRS). However, the causative gene is not currently known. There is growing evidence that molecular changes at the imprinted MEST region in 7q32.2 are associated with a phenotype evocative of SRS. This report details a patient with a SRS-like phenotype and a paternally inherited microdeletion of 79 kilobases (35-fold smaller than the previously reported smallest deletion) in the 7q32.2 region. This microdeletion encompasses only five genes, including MEST, which corroborates the hypothesis that MEST plays a central role in the 7q32.2 microdeletion growth disorder, as well as further implicating MEST in upd(7)mat SRS itself.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/173115/1/ajmga62782.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/173115/2/ajmga62782_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/173115/3/ajmga62782-sup-0001-FigureS1.pd

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure - Fig 4

<p>Brain volume Z scores and normed head circumference (HC) standard deviations are shown to positively correlate in both the control (A) and prenatal alcohol exposure (PAE) groups (B).</p

When only including the 14 PAE participants below the clinical cutoff for microcephaly (HC ≤ 3^rd percentile, A–column 1), it is notable that 10 (~70%) of the subjects have brain volumes below the 3^rd percentile.

<p>Similarly, ~80% of the subjects with HC ≤ 10^th percentile have brain volumes under the 10^th percentile (A–column 2). Conversely, among the PAE participants with total brain volume ≤ 3^rd (n = 14, B–column 1) or 10^th percentile (n = 22, B—column 2), 55–65% of subjects have HC in the ‘normal’ range from the 11^th-99th percentiles, suggesting a disconnect between small brain volumes and head circumference. Note that the category of ≤ 10^th percentile on the x-axis of A and B includes subjects who are ≤ 3^rd percentile (to match cutoffs used in various diagnostic guidelines), while colour divisions within each bar are non-overlapping.</p