DNA methylation signatures of early-life adversity are exposure-dependent in wild baboons.

The early-life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early-life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early-life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early-life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early-life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early-life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early-life effects on fitness-related traits.

Mechanisms, predictors, and evolution of severe peri-device leaks with two different left atrial appendage occluders.

AIMS: Incomplete left atrial appendage occlusion (LAAO) due to peri-device leak (PDL) is a limitation of the therapy. The Amulet IDE trial is the largest randomized head-to-head trial comparing the Amulet and Watchman 2.5 LAAO devices with fundamentally different designs. The predictors and mechanistic factors impacting differences in PDLs within the Amulet IDE trial are assessed in the current analysis. METHODS AND RESULTS: An independent core lab analysed all images for the presence or absence of severe PDL (>5 mm). The incidence, mechanistic factors, predictors using propensity score-matched controls, and evolution of severe PDLs through 18 months were assessed. Of the 1878 patients randomized in the trial, the Amulet occluder had significantly fewer severe PDLs than the Watchman device at 45 days (1.1 vs. 3.2%, P < 0.001) and 12 months (0.1 vs. 1.1%, P < 0.001). Off-axis deployment or missed lobes were leading mechanistic PDL factors in each device group. Larger left atrial appendage (LAA) dimensions including orifice diameter, landing zone diameter, and depth predicted severe PDL with the Watchman device, with no significant anatomical limitations noted with the Amulet occluder. Procedural and device implant predictors were found with the Amulet occluder attributed to the learning curve with the device. A majority of Watchman device severe PDLs did not resolve over time through 18 months. CONCLUSION: The dual-occlusive Amplatzer Amulet LAA occluder provided improved LAA closure compared with the Watchman 2.5 device. Predictors and temporal observations of severe PDLs were identified in the Amulet IDE trial. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov Unique identifier NCT02879448.

Sparrows and supergenes: Ecological epigenetics in action.

Despite the promise of ecological epigenetics, there remain few cases that clearly link epigenetic variation in wild animal populations to evolutionary change. In this issue of Molecular Ecology, Sun et al. provide such an example in white-throated sparrows-a fascinating system in which a large chromosomal rearrangement generates a "supergene" polymorphism linked to plumage colour, aggression and parenting behaviour. By combining whole genome bisulphite sequencing with RNA-sequencing and chromatin accessibility data, they show that the two alleles of this chromosomal polymorphism also exhibit substantial differences in DNA methylation levels, with implications for gene expression and transposable element activity. Their results provide a compelling case study for how genetic and epigenetic evolution proceed in concert. They also demonstrate the importance of integrating multiple types of genomic information to understand how gene regulation evolves, providing a model for future work in nonmodel species.

Development of drug-coated balloon for the treatment of multiple peripheral artery segments.

OBJECTIVE: Peripheral artery disease is the second most common cardiovascular disease. It can often occur in complex form when there is a presence of long, diffuse, and multiple lesions. Current treatments use either single long drug-coated balloons (DCBs) or multiple DCBs; however, treatment success is limited. The purpose of this study was to investigate the preclinical feasibility of our multiple-release Tailored Medical Devices DCB (MR-TMD-DCB) to treat multiple arterial segments using a single DCB. METHODS: The MR-TMD-DCBs were developed using a two-layer coating approach. The DCBs were developed in a certified Current Good Manufacturing Practices facility using presterilized materials and reagent and then characterized for coating morphology, thermal and chemical changes, and in vitro particulate shedding. The drug loss, tissue uptake, and undelivered drug amounts were analyzed using an in vitro peripheral artery flow model and explanted pig arteries. Then, an in vivo survival study was performed using a healthy porcine model to measure the short-term drug uptake (seven swine; 14 treatments at day 1) and retention (seven swine; 14 treatments at day 7) in two different arterial segments after treatment with a single MR-TMD-DCB. RESULTS: The coating on the MR-TMD-DCB was smooth and homogeneous with paclitaxel molecularly dispersed in its amorphous state. A negligible number of particulates were shed from the MR-TMD-DCB coating. A similar amount of drug was accurately delivered into two separate explanted arteries using a single MR-TMD-DCB during the in vitro flow model testing (707 ± 109 ng/mg in the first explanted artery and 783 ± 306 ng/mg in the second explanted artery). The MR-TMD-DCB treatment resulted in equivalent drug amounts in the two arterial segments at day 1 (63 ± 19 ng/mg in the first treatment site and 59 ±19 ng/mg in the second treatment site) and at day 7 (9 ± 6 ng/mg in the first treatment site and 10 ± 6 ng/mg in the second treatment site). In addition, the drug levels at each time point were in the clinically relevant range to prevent neointimal hyperplasia. CONCLUSIONS: The MR-TMD-DCBs provided equivalent and clinically relevant drug retention levels into two different arterial segments. Thus, MR-TMD-DCBs can be used to accurately deliver drug into multiple arterial segments with the use of a single DCB. The clinical outcomes of these findings need further investigation. Future long-term pharmacokinetics and safety studies will be performed to evaluate the safety and efficacy of the MR-TMD-DCB.

In vitro particulate and in vivo drug retention study of a novel polyethylene oxide formulation for drug-coated balloons.

OBJECTIVE: The purpose of this study was to investigate the newly developed drug-coated balloon (DCB) using polyethylene oxide (PEO) as a platform and to compare it directly with a commercially available DCB in a preclinical experimental setting. METHODS: The PEO balloon was characterized for coating morphology and degree of paclitaxel (PAT) crystallinity. PAT tissue levels were then measured up to 30 days in a healthy porcine model (10 swine, 20 vessels) after treatment with either a PEO balloon or a commercially available DCB. An in vitro bench-top model was used to compare the particulates released from the PEO balloon and commercially available DCB. RESULTS: The coating on the PEO balloon was smooth and homogeneous with PAT in its amorphous state. From the porcine survival study, the PAT tissue levels were comparable between PEO balloon and commercially available DCB after 7 days of treatment. Both the PEO balloon and the commercially available DCB retained therapeutic drug up to 30 days. During the simulated in vitro model, the PEO balloon shed significantly fewer particulates that were smaller than those of the commercially available DCB. Most important, the PEO balloon shed 25 times fewer large particulates than the commercially available DCB. CONCLUSIONS: The amorphous PAT in the PEO balloon provided comparable drug tissue retention levels to those of the commercially available DCB and fewer particulates. Thus prepared PEO balloon proved to be safe and effective in the preclinical experimental setting. The clinical outcomes of these findings need further investigation.

Feasibility of Amulet occluder implantation after failed left atrial appendage occlusion attempt: Insights from the EMERGE LAA postapproval study.

BACKGROUND: Although expertise in left atrial appendage occlusion (LAAO) has grown, certain intricate anatomies may pose challenges, rendering them unsuitable for LAAO with the selected device. OBJECTIVE: This analysis aimed to characterize outcomes of patients with prior failed percutaneous LAAO procedures who underwent a subsequent attempt with an Amulet occluder in the EMERGE LAA postapproval study. METHODS: Patients enrolled in the National Cardiovascular Data Registry LAAO Registry who had an Amulet occluder implantation attempt between Food and Drug Administration approval (August 14, 2021) and June 30, 2023, were evaluated. A safety end point through 7 days or hospital discharge (whichever was later) and major adverse events through 45 days were reported. RESULTS: A total of 8591 patients underwent attempted Amulet occluder implantation, of whom 244 patients had prior failed LAAO. Implantation success was 88.9% and 96.2% in patients with prior failed LAAO and index LAAO, respectively (P < .001). The safety composite end point was low, occurring in 1.6% and 0.8% of patients with prior failed LAAO and index LAAO, respectively (P = .148). Any major adverse event through 45 days occurred in 7.4% and 6.3% of prior failed LAAO and index LAAO patient cohorts, respectively (P = .497); most adverse events were similar between the groups (P > .05). At 45 days, peridevice leak ≤3 mm was achieved in >90% of patients in either group. CONCLUSION: A high degree of implantation success with a low rate of adverse events can be achieved with the Amulet occluder. The findings imply that the dual occlusive mechanism Amulet occluder facilitates successful closure, even in challenging anatomic scenarios.

DNA methylation signatures of early life adversity are exposure-dependent in wild baboons.

The early life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early life effects on fitness-related traits.

3-Year Outcomes From the Amplatzer Amulet Left Atrial Appendage Occluder Randomized Controlled Trial (Amulet IDE).

BACKGROUND: The Amulet (Abbott) left atrial appendage occluder investigational device exemption trial is the largest randomized trial evaluating the safety and effectiveness of the Amulet left atrial appendage occluder compared with the Watchman 2.5 device (Boston Scientific) through 5 years. OBJECTIVES: This analysis evaluated the device effect on 3-year outcomes in the Amulet investigational device exemption trial. METHODS: The medication regimen and key clinical outcomes were reported through 3 years including: 1) the composite of ischemic stroke or systemic embolism (SE); 2) the composite of all strokes, SE, or cardiovascular (CV) death; 3) major bleeding; and 4) all-cause death and CV death. RESULTS: A total of 1,878 patients at 108 sites were randomized. A significantly higher percentage of patients were free of oral anticoagulation usage at 3 years with Amulet (96.2%) vs Watchman (92.5%) (P < 0.01). Clinical outcomes were comparable for the composite of ischemic stroke or SE (5.0% vs 4.6%; P = 0.69); the composite of all strokes, SE, or CV death (11.1% vs 12.7%; P = 0.31); major bleeding (16.1% vs 14.7%; P = 0.46); all-cause death (14.6% vs 17.9%; P = 0.08); and CV death (6.6% vs 8.5%; P = 0.14) for Amulet and Watchman, respectively. Through 3 years, device factors (device-related thrombus or peridevice leak ≥3 mm) preceded ischemic stroke events and CV deaths more frequently in Watchman compared with Amulet patients. CONCLUSIONS: The Amulet occluder demonstrated continued safety and effectiveness with over 96% free of oral anticoagulation usage through 3 years in a high-risk population compared to the Watchman device. (AMPLATZER Amulet LAA Occluder Trial [Amulet IDE]; NCT02879448).

Incidence, Predictors, and Clinical Outcomes of Device-Related Thrombus in the Amulet IDE Trial.

BACKGROUND: Device-related thrombus (DRT) following left atrial appendage occlusion (LAAO) can lead to adverse clinical outcomes. DRT rates and outcomes from randomized trials are limited. OBJECTIVES: This analysis investigated the incidence, predictors, and clinical outcomes of DRT following LAAO in the Amulet IDE (AMPLATZER Amulet LAA Occluder Trial) trial. METHODS: Successful implants occurred in 903 patients with an Amulet occluder (dual occlusive mechanism device) and 885 patients with a Watchman device (single occlusive mechanism device). These patients were then followed through 18 months and DRT was assessed by transesophageal echocardiography. RESULTS: The overall incidence of DRT was 3.9% (n = 70) with 3.4% (n = 30) in dual occlusive mechanism device patients and 4.8% (n = 40) in single occlusive mechanism device patients. Most DRTs (n = 19 of 31) were identified early (≤45 days) on the dual occlusive mechanism device, whereas most of the DRTs (n = 31 of 42) were identified late (>45 days) on the single occlusive mechanism device. Strong predictors of DRT included atrial fibrillation at time of procedure (HR: 2.44; 95% CI: 1.42-4.22; P < 0.01), female sex (HR: 1.65; 95% CI: 1.01-2.71; P = 0.04), and older age (HR: 1.04; 95% CI: 1.01-1.08; P = 0.02). There were no stroke events following DRT in the dual occlusive mechanism device group and 3 stroke events following DRT in the single occlusive mechanism device group. Patients with DRT were at a greater risk for cardiovascular mortality compared with non-DRT patients (8.7% vs 3.9%; HR: 2.33; 95% CI: 1.01-5.39; P = 0.04). CONCLUSIONS: Incidence of DRT following LAAO was low. Early DRTs are seen with the dual occlusive mechanism device and late DRTs are seen with the single occlusive mechanism device. Increased cardiovascular mortality risk in patients with DRT should be further investigated. (AMPLATZER Amulet LAA Occluder Trial; NCT02879448).

Sex Differences in Safety and Effectiveness of LAAO: Insights From the Amulet IDE Trial.

BACKGROUND: Women have higher rates of acute complications after left atrial appendage occlusion (LAAO). However, data on long-term safety and effectiveness are limited. OBJECTIVES: The aim of this study was to examine sex-specific short- and long-term outcomes after LAAO in the Amulet IDE (Amplatzer™ Amulet™ LAA Occluder) trial. METHODS: The following outcomes were compared between men and women: in-hospital complications, device-related outcomes (peridevice leak at 45 days and device-related thrombus at 18 months), and long-term clinical outcomes (death, thromboembolism, and bleeding). Subanalyses for the interaction between sex and device type were performed. RESULTS: A total of 1,833 patients underwent attempted device implantation (917 with the Amulet and 916 with the Watchman), of whom 734 were women (40%). Device success was 97.4% in men and 97.1% in women (P = 0.60). Rates of major in-hospital adverse events were higher in women (4.4% vs 1.9%; P < 0.01), driven by major bleeding (3.7% vs 1.0%; P < 0.01) and pericardial effusion requiring intervention (2.0% vs 0.5%; P < 0.01). Peridevice leak and device-related thrombus were similar in men and women (18.3% vs 18.9% [P = 0.78] and 3.3% vs 5.0% [P = 0.10], respectively). There were no differences between men and women in rates of ischemic stroke or systemic embolism (2.6% vs 2.6%; P = 0.98), transient ischemic attack (1.3% vs 1.6%; P = 0.69), hemorrhagic stroke (0.5% vs 0.4%; P = 0.88), major bleeding (10.1% vs 10.9%; P = 0.49), cardiovascular death (4.3% vs 3.5%; P = 0.45), or all-cause death (8.9% vs 6.9%; P = 0.16). CONCLUSIONS: In the Amulet IDE trial, long-term clinical outcomes including effectiveness following LAAO were comparable in men and women despite the higher rates of in-hospital complications due to major bleeding and pericardial effusion in women. (Amplatzer™ Amulet™ LAA Occluder Trial [Amulet IDE]; NCT02879448).

Peridevice Leak After Transcatheter Left Atrial Appendage Occlusion: An Analysis of the Amulet IDE Trial.

BACKGROUND: Peridevice leak (PDL) is a limitation of left atrial appendage occlusion. OBJECTIVES: The aim of this study was to assess the incidence of and outcomes associated with PDL in the Amulet IDE (AMPLATZER™ Amulet™ LAA Occluder Trial) randomized controlled trial. METHODS: Patients with atrial fibrillation at increased stroke risk were randomly assigned to undergo either Amulet (dual occlusive mechanism) or Watchman 2.5 (single occlusive mechanism) device implantation. Transesophageal echocardiography was performed at 45 days and 12 months postprocedure. Clinically significant PDL was defined as ≥3 mm. The primary endpoint was ischemic stroke or systemic embolism, and the secondary endpoint was stroke, systemic embolism, or cardiovascular death. The Kaplan-Meier method was used to estimate 18-month cumulative event rates landmarked at day 45 postprocedure. RESULTS: A total of 1,593 patients underwent successful left atrial appendage occlusion and had an evaluable transesophageal echocardiographic studies at 45 days. The dual-occlusive mechanism device provided superior closure (defined as leak <3 mm) compared with the single-occlusive mechanism device at 45 days (88.9% vs 74.1%; P < 0.01) and 12 months (90.5% vs. 78.3%; P < 0.01). Through 18 months, PDL was associated with a higher, but not statistically significant, risk for the primary endpoint (3.6% vs 1.8%; adjusted HR: 1.98; 95% CI: 0.93-4.19; P = 0.07) and a statistically significantly higher risk for the secondary endpoint (8.1% vs. 4.7%; adjusted HR: 1.66; 95% CI: 1.02-2.69; P = 0.04). CONCLUSIONS: The dual-occlusive mechanism device provided superior closure compared with the single-occlusive mechanism device at both 45 days and 1 year postprocedure. PDL ≥3 mm was associated with a significantly increased 18-month risk for the composite of stroke, systemic embolism, or cardiovascular death. Completeness of closure of the left atrial appendage has important implications for patient outcomes. (AMPLATZER™ Amulet™ LAA Occluder Trial [Amulet IDE]; NCT02879448).

Distinct gene regulatory signatures of dominance rank and social bond strength in wild baboons.

The social environment is a major determinant of morbidity, mortality and Darwinian fitness in social animals. Recent studies have begun to uncover the molecular processes associated with these relationships, but the degree to which they vary across different dimensions of the social environment remains unclear. Here, we draw on a long-term field study of wild baboons to compare the signatures of affiliative and competitive aspects of the social environment in white blood cell gene regulation, under both immune-stimulated and non-stimulated conditions. We find that the effects of dominance rank on gene expression are directionally opposite in males versus females, such that high-ranking males resemble low-ranking females, and vice versa. Among females, rank and social bond strength are both reflected in the activity of cellular metabolism and proliferation genes. However, while we observe pronounced rank-related differences in baseline immune gene activity, only bond strength predicts the fold-change response to immune (lipopolysaccharide) stimulation. Together, our results indicate that the directionality and magnitude of social effects on gene regulation depend on the aspect of the social environment under study. This heterogeneity may help explain why social environmental effects on health and longevity can also vary between measures. This article is part of the theme issue 'The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies'.

Outcomes of the roll-in cohort of the Amulet IDE trial of left atrial appendage occlusion.

Background: Left atrial appendage (LAA) occlusion is an alternative therapy to oral anticoagulants to reduce stroke risk in patients with nonvalvular atrial fibrillation (NVAF). The Amulet IDE trial compared the Amplatzer™ Amulet™ occluder (Abbott) with the Watchman™ 2.5 device (Boston Scientific) for LAA occlusion in patients with NVAF. Objective: The purpose of this study was to describe outcomes of the Amulet IDE trial roll-in cohort. Methods: At US sites up to 3 patients per implanter could be implanted with the Amulet occluder in the roll-in phase. The primary Endpoints in the Amulet IDE trial included safety (composite of procedure-related complications, all-cause death, or major bleeding at 12 months), effectiveness (composite of ischemic stroke or systemic embolism at 18 months), and rate of LAA occlusion at 45 days. Results: A total of 201 roll-in patients were enrolled. Device success occurred in 99% of patients, and device closure (residual jet ≤5 mm) was observed in 98.9% of patients at 45 days. The safety endpoint rate was numerically higher (worse) in the roll-in cohort compared to the randomized Amulet occluder cohort (18.4% vs 14.5%). Six patients (3.1%) experienced an ischemic stroke and 0 patients with a systemic embolism within 18 months, which was similar to the primary effectiveness endpoint rate in the randomized Amulet occluder cohort (2.8%). Conclusions: Despite lack of experience of the operators with the Amulet occluder in the roll-in phase, device implant success was high, a high rate of device closure was achieved, and low stroke rates were observed in patients with NVAF.

Selection against admixture and gene regulatory divergence in a long-term primate field study.

Genetic admixture is central to primate evolution. We combined 50 years of field observations of immigration and group demography with genomic data from ~9 generations of hybrid baboons to investigate the consequences of admixture in the wild. Despite no obvious fitness costs to hybrids, we found signatures of selection against admixture similar to those described for archaic hominins. These patterns were concentrated near genes where ancestry is strongly associated with gene expression. Our analyses also show that introgression is partially predictable across the genome. This study demonstrates the value of integrating genomic and field data for revealing how "genomic signatures of selection" (e.g., reduced introgression in low-recombination regions) manifest in nature; moreover, it underscores the importance of other primates as living models for human evolution.

Behavioral mimicry predicts social favor in adolescent rhesus macaques (Macaca mulatta).

Non-conscious mimicry is a highly conserved component of animal behavior with multifaceted connections to sociality across taxa. One intriguing consequence of this mimicry in primates is that it promotes positive social feedback from the recipient toward the mimicker. This suggests that mimicry in primates may be an important aspect of positive social interaction, but few studies have tracked the consequences of mimicry in naturally occurring complex social conditions. Here, we designed a novel ethogram to characterize mimicry between conspecifics, to better understand whether mimicry is associated with affiliation between primates in a semi-naturalistic captive setting. In this study, 15 juvenile (aged 2-4 years) rhesus macaques (Macaca mulatta) were observed at the California National Primate Research Center. Frequencies of mimicry defined a priori (e.g. following, postural mimicry) were observed over a course of 12 weeks. In separate observations during the same period, focal social behavior (e.g. aggression, play, affiliation) with group members was also observed. Subjects that exhibited higher degrees of mimicry were not more prosocial, but they received significantly more play overtures from social partners (p < 0.01). Additionally, rates of mimicry were higher in 2- and 3-year-olds than 4-year-olds. These results provide proof of principle in a small sample of monkeys that mimicry is associated with social advantages in a complex, semi-naturalistic setting in primates.

High social status males experience accelerated epigenetic aging in wild baboons.

Aging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting 'epigenetic clock' closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons - the best predictor of reproductive success - imposes costs consistent with a 'live fast, die young' life-history strategy.

For most animals, age is one of the strongest predictors of health and survival, but not all individuals age at the same rate. In fact, animals of the same species can have different 'biological ages' even when they have lived the same number of years. In humans and other mammals this variation in aging shows up in chemical modifications known as DNA methylation marks. Some researchers call these marks 'epigenetic', which literally means 'upon the genes'. And some DNA methylation marks change with age, so their combined pattern of change is often called the 'epigenetic clock'. Environmental stressors, such as smoking or lack of physical activity, can make the epigenetic clock 'tick' faster, making the DNA of some individuals appear older than expected based on their actual age in years. These 'biologically older' individuals may also experience a higher risk of age-related disease. Studies in humans have revealed some of the reasons behind this fast biological aging, but it is unclear whether these results apply in the wild. It is possible that early life events trigger changes in the epigenetic clock, affecting health in adulthood. In primates, for example, adversity in early life has known effects on fertility and survival. Low social status also has a negative effect on health. To find out whether early experiences and the social environment affect the epigenetic clock, Anderson, Johnston et al. tracked DNA methylation marks in baboons. This revealed that epigenetic clocks are strong predictors of age in wild primates, but neither early adversity nor the strength of social bonds affected the rate at which the clocks ticked. In fact, it was competition for social status that had the most dramatic effect on the clock's speed. Samples of males taken at different times during their lives showed that their epigenetic clocks sped up or slowed down as they moved up or down the social ladder, reflecting recent social experiences, rather than events early in their lives. On average, epigenetic clock measurements overestimated the age in years of alpha males by almost a year, showing that fighting to be on top comes at a cost. This study highlights one way in which the social environment can influence aging. The next step is to understand how health is affected by the ways that animals attain social status. This could help researchers who study evolution understand how social interactions and environmental conditions affect survival and reproduction. It could also provide insight into the effects of social status on human health and aging.

Broadening primate genomics: new insights into the ecology and evolution of primate gene regulation.

Comparative analyses have played a key role in understanding how gene regulatory evolution contributes to primate phenotypic diversity. Recently, these studies have expanded to include a wider range of species, within-population as well as interspecific analyses, and research on wild as well as captive individuals. This expansion provides context for understanding genetic and environmental effects on gene regulation in humans, including the importance of the pathogen and social environments. Although taxonomic representation remains biased, inclusion of more species has also begun to reveal the evolutionary processes that explain whether and when gene regulation is conserved. Together, this work highlights how studies in other primates contribute to understanding evolution in our own lineage, and we conclude by identifying promising avenues for future work.

Development of an automated micropipette coating method for drug-coated balloons.

Drug-coated balloons (DCBs) are a recent technology developed to treat peripheral artery disease (PAD). Along with a suitable formulation of antiproliferative drug and excipient, coating method is an important aspect of a DCB as these factors affect coating characteristics and drug delivery to the treatment site. The multiple release tailored medical devices DCB (MR-TMD-DCB), designed to achieve multiple inflations to treat complex PAD, contains paclitaxel (PAT) as the antiproliferative drug and polyethylene oxide (PEO) as the excipient. In our previous studies, the MR-TMD-DCB was coated using a manual dip coating method. In this study, an automated micropipette coating method was developed using a modified spray coating instrument to coat the MR-TMD-DCB. First, the coating formulation and strategy was optimized. A drug formulation of 16 wt% PAT and 4% wt/vol PEO, a polymer formulation of 2.5% wt/vol PEO, and a total of two drug layers produced a mostly uniform and thin coating with no defects and acceptable drug load. The balloon also had optimal drug uptake in arterial tissue in an in vitro flow model. Next, the reproducibility of the coating strategy was improved by optimizing the instrument parameters. The optimized instrument parameters (translational speed = 0.150 in/s, revolution rate = 100 rpm, flow rate = 0.6 ml/min) resulted in improved reproducibility of the drug load and similar coating properties as the DCB. This study demonstrated the ability to automate the micropipette process to obtain a balloon with optimal coating properties and drug tissue uptake.

Determining the cross-talk between smooth muscle cells and macrophages on a cobalt-chromium stent material surface using an in vitro postimplantation coculture model.

Smooth muscle cells (SMCs) and macrophages are important cellular components involved in the development of complications following the implantation of cardiovascular devices. This leads to various disorders such as restenosis, chronic inflammation, and may ultimately result in device failure. In this study, we developed a postimplant stent coculture model using different ratios of SMCs and macrophages seeded on to cobalt-chromium alloy. The macrophages had an increased affinity to the coculture surfaces, which resulted in decreased SMC attachment to the alloy surfaces at the initial time point. Once adhered, the macrophages spread freely and displayed advanced stages of inflammation at 48 h when cocultured with SMCs. This resulted in an increased secretion of proinflammatory cytokines (tumor necrosis factor alpha, monocyte chemotactic protein 1, interleukin [IL]-6, and IL-8) by 48 h in the coculture samples with the greatest increase observed with the high number of macrophages. Therefore, the increased levels of proinflammatory cytokines promoted the growth of SMCs in coculture to a greater extent than when the SMCs were culture alone. Thus, this study demonstrated the constant cross-talk between SMCs and macrophages occurring on the postimplant stent surface. Similar coculture models can be used to test the biocompatibility of drugs and biomaterials at possible postimplantation scenarios. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 673-685, 2018.