Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.

BACKGROUND: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. METHODS: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. RESULTS: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. CONCLUSIONS: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

Frailty and cardiovascular mortality in more than 3 million US Veterans.

AIMS: Frailty is associated with an increased risk of all-cause mortality and cardiovascular (CV) events. Limited data exist from the modern era of CV prevention on the relationship between frailty and CV mortality. We hypothesized that frailty is associated with an increased risk of CV mortality. METHODS AND RESULTS: All US Veterans aged ≥65 years who were regular users of Veteran Affairs care from 2002 to 2017 were included. Frailty was defined using a 31-item previously validated frailty index, ranging from 0 to 1. The primary outcome was CV mortality with secondary analyses examining the relationship between frailty and CV events (myocardial infarction, stroke, revascularization). Survival analysis models were adjusted for age, sex, ethnicity, geographic region, smoking, hyperlipidaemia, statin use, and blood pressure medication use. There were 3 068 439 US Veterans included in the analysis. Mean age was 74.1 ± 5.8 years in 2002, 76.0 ± 8.3 years in 2014, 98% male, and 87.5% White. In 2002, the median (interquartile range) frailty score was 0.16 (0.10-0.23). This increased and stabilized to 0.19 (0.10-0.32) for 2006-14. The presence of frailty was associated with an increased risk of CV mortality at every stage of frailty. Frailty was associated with an increased risk of myocardial infarction and stroke, but not revascularization. CONCLUSION: In this population, both the presence and severity of frailty are tightly correlated with CV death, independent of underlying CV disease. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished. KEY QUESTION: Can an electronic frailty index identify adults aged 65 and older who are at risk of CV mortality and major CV events? KEY FINDING: Among 3 068 439 US Veterans aged 65 and older, frailty was associated with an increased risk of CV mortality at every level of frailty. Frailty was also associated with an increased risk of myocardial infarction and stroke, but not revascularization. TAKE HOME MESSAGE: Both the presence and severity of frailty are associated with CV mortality and major CV events, independent of underlying CV disease.

Impact of Coronavirus Disease 2019 (COVID-19) Severity on Long-term Events in United States Veterans Using the Veterans Affairs Severity Index for COVID-19 (VASIC).

In this retrospective cohort study of 94 595 severe acute respiratory syndrome coronavirus 2-positive cases, we developed and validated an algorithm to assess the association between coronavirus disease 2019 (COVID-19) severity and long-term complications (stroke, myocardial infarction, pulmonary embolism/deep vein thrombosis, heart failure, and mortality). COVID-19 severity was associated with a greater risk of experiencing a long-term complication 31-120 days postinfection. Most incident events occurred 31-60 days postinfection and diminished after day 91, except heart failure for severe patients and death for moderate patients, which peaked on days 91-120. Understanding the differential impact of COVID-19 severity on long-term events provides insight into possible intervention modalities and critical prevention strategies.

Low Blood Pressure, Comorbidities, and Ischemic Stroke Mortality in US Veterans.

BACKGROUND AND PURPOSE: Low blood pressure (BP) is associated with higher stroke mortality, although the factors underlying this association have not been fully explored. We investigated prestroke BP and long-term mortality after ischemic stroke in a national sample of US veterans. METHODS: Using a retrospective cohort study design of veterans hospitalized between 2002 and 2007 with a first ischemic stroke and with ≥1 outpatient BP measurements 1 to 18 months before admission, we defined 6 categories each of average prestroke systolic BP (SBP) and diastolic BP, and 7 categories of pulse pressure. Patients were followed-up to 12 years for primary outcomes of all-cause and cardiovascular mortality. We used Cox models to relate prestroke BP indices to mortality and stratified analyses by the presence of preexisting comorbidities (smoking, myocardial infarction, heart failure, atrial fibrillation/flutter, cancer, and dementia), race and ethnicity. RESULTS: Of 29 690 eligible veterans with stroke (mean±SD age 67±12 years, 98% men, 67% White), 2989 (10%) had average prestroke SBP<120 mm Hg. During a follow-up of 4.1±3.3 years, patients with SBP<120 mm Hg experienced 61% all-cause and 27% cardiovascular mortality. In multivariable analyses, patients with the lowest SBP, lowest diastolic BP, and highest pulse pressure had the highest mortality risk: SBP<120 versus 130 to 139 mm Hg (hazard ratio=1.26 [95% CI, 1.19-1.34]); diastolic BP <60 versus 70 to 79 mm Hg (hazard ratio=1.35 [95% CI, 1.23-1.49]); and pulse pressure ≥90 versus 60 to 69 mm Hg (hazard ratio=1.24 [95% CI, 1.15-1.35]). Patients with average SBP<120 mm Hg and at least one comorbidity (smoking, heart disease, cancer, or dementia) had the highest mortality risk (hazard ratio=1.45 [95% CI, 1.37-1.53]). CONCLUSIONS: Compared with normotension, low prestroke BP was associated with mortality after stroke, particularly among patients with at least one comorbidity.

Hexabothriidae and Monocotylidae (Monogenoidea) from the gills of neonate hammerhead sharks (Sphyrnidae) Sphyrna gilberti, Sphyrna lewini and their hybrids from the western North Atlantic Ocean.

Neonates of hammerhead sharks (Sphyrnidae), Sphyrna lewini (Griffith and Smith, 1834), the sympatric cryptic species, Sphyrna gilberti Quattro et al., 2013, and their hybrids were captured in the western North Atlantic, along the coast of South Carolina, USA, between 2018 and 2019 and examined for gill monogenoids. Parasites were identified and redescribed from the gills of 79 neonates, and DNA sequences from partial fragments of the nuclear 28S ribosomal RNA (rDNA) and cytochrome c oxidase I mitochondrial DNA (COI) genes were generated to confirm species identifications. Three species of monogenoids from Hexabothriidae Price, 1942 and Monocotylidae Taschenberg, 1879 were determined and redescribed. Two species of Hexabothriidae, Erpocotyle microstoma (Brooks, 1934) and Erpocotyle sphyrnae (MacCallum, 1931), infecting both species of Sphyrna and hybrids; and 1 species of Monocotylidae, Loimosina wilsoni Manter, 1944, infecting only S. lewini and hybrids. Loimosina wilsoni 28S rDNA sequences matched those of Loimosina sp. from the southern coast of Brazil. Based on limited morphological analysis, Loimosina parawilsoni is likely a junior synonym of L. wilsoni. This is the first taxonomic study of monogenoids infecting S. gilberti and hybrids of S. gilberti and S. lewini.

Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization.

The fumarate ester dimethyl fumarate (DMF) has been introduced recently as a treatment for relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition that results in neuronal demyelination and axonal loss. DMF is known to act by depleting intracellular glutathione and modifying thiols on Keap1 protein, resulting in the stabilization of the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. We have previously shown that DMF reacts with a wide range of protein thiols, suggesting that the complete mechanisms of action of DMF are unknown. Here, we investigated other intracellular thiol residues that may also be irreversibly modified by DMF in neurons and astrocytes. Using mass spectrometry, we identified 24 novel proteins that were modified by DMF in neurons and astrocytes, including cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). Using an in vitro functional assay, we demonstrated that DMF-modified cofilin-1 loses its activity and generates less monomeric actin, potentially inhibiting its cytoskeletal remodeling activity, which could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. We found that the oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, our work provides new insights into the mechanisms supporting the neuroprotective and remyelination benefits associated with DMF treatment in addition to the antioxidant response by Nrf2.

Historic Assessment and Analysis of the Mass Production of Laricobius spp. (Coleoptera: Derodontidae), Biological Control Agents for the Hemlock Woolly Adelgid, at Virginia Tech.

Laricobius nigrinus (Coleoptera: Derodontidae) Fender and Laricobius osakensis (Coleoptera: Derodontidae) Montgomery and Shiyake have been mass produced by Virginia Tech as biological control agents for the hemlock woolly adelgid (HWA), Adelges tsugae (Hemiptera: Adelgidae) Annand, for the past 15 and 9 yr, respectively. Herein, we describe modifications of our rearing procedures, trends and analyses in the overall production of these agents, and the redistribution of these agents for release to local and federal land managers. Based on these data, we have highlighted three major challenges to the rearing program: 1) high mortality during the subterranean portion of its life cycle (averaging 37% annually) reducing beetle production, 2) asynchrony in estivation emergence relative to the availability of their host HWA minimizing food availability, and 3) unintended field collections of Laricobius spp. larvae on HWA provided to lab-reared larvae complicating rearing procedures. We further highlight corresponding avenues of research aimed at addressing each of these challenges to further improve Laricobius spp. production.

First record of Piscicapillaria bursata (Nematoda: Capillariidae), a parasite of hammerhead sharks Sphyrna spp., in the western Atlantic Ocean.

Examination of 32 spiral valves from neonate specimens of hammerhead shark Sphyrna spp. (Carcharhiniformes: Sphyrnidae) captured between June and August 2018 off the Atlantic coast of South Carolina, USA, revealed the presence of the capillariid nematode Piscicapillaria bursata (Capillariidae) in the Carolina hammerhead S. gilberti, the scalloped hammerhead S. lewini, and their hybrids. This is the second find of this parasite originally described from hammerhead sharks off Australia, its first record from the western Atlantic Ocean, and its first record in a new host species and in hybrids.

Association of Statin Use With All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older.

Importance: Data are limited regarding statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in adults 75 years and older. Objective: To evaluate the role of statin use for mortality and primary prevention of ASCVD in veterans 75 years and older. Design, Setting, and Participants: Retrospective cohort study that used Veterans Health Administration (VHA) data on adults 75 years and older, free of ASCVD, and with a clinical visit in 2002-2012. Follow-up continued through December 31, 2016. All data were linked to Medicare and Medicaid claims and pharmaceutical data. A new-user design was used, excluding those with any prior statin use. Cox proportional hazards models were fit to evaluate the association of statin use with outcomes. Analyses were conducted using propensity score overlap weighting to balance baseline characteristics. Exposures: Any new statin prescription. Main Outcomes and Measures: The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes included a composite of ASCVD events (myocardial infarction, ischemic stroke, and revascularization with coronary artery bypass graft surgery or percutaneous coronary intervention). Results: Of 326 981 eligible veterans (mean [SD] age, 81.1 [4.1] years; 97% men; 91% white), 57 178 (17.5%) newly initiated statins during the study period. During a mean follow-up of 6.8 (SD, 3.9) years, a total 206 902 deaths occurred including 53 296 cardiovascular deaths, with 78.7 and 98.2 total deaths/1000 person-years among statin users and nonusers, respectively (weighted incidence rate difference [IRD]/1000 person-years, -19.5 [95% CI, -20.4 to -18.5]). There were 22.6 and 25.7 cardiovascular deaths per 1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, -3.1 [95 CI, -3.6 to -2.6]). For the composite ASCVD outcome there were 123 379 events, with 66.3 and 70.4 events/1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, -4.1 [95% CI, -5.1 to -3.0]). After propensity score overlap weighting was applied, the hazard ratio was 0.75 (95% CI, 0.74-0.76) for all-cause mortality, 0.80 (95% CI, 0.78-0.81) for cardiovascular mortality, and 0.92 (95% CI, 0.91-0.94) for a composite of ASCVD events when comparing statin users with nonusers. Conclusions and Relevance: Among US veterans 75 years and older and free of ASCVD at baseline, new statin use was significantly associated with a lower risk of all-cause and cardiovascular mortality. Further research, including from randomized clinical trials, is needed to more definitively determine the role of statin therapy in older adults for primary prevention of ASCVD.

Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes.

Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. We found that extracellular dopamine triggered rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. This was accompanied by reduced duration and increased frequency of astrocytic Ca2+ transients, but little effect on astrocytic voltage-gated potassium channel currents. To isolate possible mechanisms underlying these structural and functional changes, we used whole-genome RNA sequencing and found prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) motif, suggesting involvement of chromatin restructuring in the nucleus. CTCF binding to promoter sites bidirectionally regulates gene transcription and depends on activation of poly-ADP-ribose polymerase 1 (PARP1). Accordingly, antagonism of PARP1 occluded dopamine-induced changes, whereas a PARP1 agonist facilitated dopamine-induced changes on its own. These results indicate that astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring and concerted expression of gene networks. Our findings propose epigenetic regulation of chromatin landscape as a critical factor in the rapid astrocyte response to dopamine.SIGNIFICANCE STATEMENT Although dopamine is widely recognized for its role in modulating neuronal responses both in healthy and disease states, little is known about dopamine effects at non-neuronal cells in the brain. To address this gap, we performed whole-genome sequencing of astrocytes exposed to elevated extracellular dopamine and combined it with evaluation of effects on astrocyte morphology and function. We demonstrate a temporally dynamic pattern of genomic plasticity that triggers pronounced changes in astrocyte morphology and function. We further show that this plasticity depends on activation of genes sensitive to DNA-binding protein CTCF. Our results propose that a broad pattern of astrocyte responses to dopamine specifically relies on CTCF-dependent gene networks.

Effects of antimicrobial use in agricultural animals on drug-resistant foodborne salmonellosis in humans: A systematic literature review.

Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant meat or dairy-borne non-typhoidal salmonellosis in humans. Based on publications from the United States (U.S.), Canada, and Denmark from January 2010 to July 2014, 858 articles received title and abstract review, 104 met study criteria for full article review with 68 retained for which data are presented. Antibiotic exposure in both cattle and humans found an increased likelihood of Salmonella colonization, whereas in chickens, animals not exposed to antibiotics (organic) were more likely to be Salmonella positive and those that had antibiotic exposure were more likely to harbor antimicrobial resistant Salmonella organisms. In swine literature, only tylosin exposure was examined and no correlation was found among exposure, Salmonella colonization, or antimicrobial resistance. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Salmonella from farm to fork.

Ancient and modern colonization of North America by hemlock woolly adelgid, Adelges tsugae (Hemiptera: Adelgidae), an invasive insect from East Asia.

Hemlock woolly adelgid, Adelges tsugae, is an invasive pest of hemlock trees (Tsuga) in eastern North America. We used 14 microsatellites and mitochondrial COI sequences to assess its worldwide genetic structure and reconstruct its colonization history. The resulting information about its life cycle, biogeography and host specialization could help predict invasion by insect herbivores. We identified eight endemic lineages of hemlock adelgids in central China, western China, Ulleung Island (South Korea), western North America, and two each in Taiwan and Japan, with the Japanese lineages specializing on different Tsuga species. Adelgid life cycles varied at local and continental scales with different sexual, obligately asexual and facultatively asexual lineages. Adelgids in western North America exhibited very high microsatellite heterozygosity, which suggests ancient asexuality. The earliest lineages diverged in Asia during Pleistocene glacial periods, as estimated using approximate Bayesian computation. Colonization of western North America was estimated to have occurred prior to the last glacial period by adelgids directly ancestral to those in southern Japan, perhaps carried by birds. The modern invasion from southern Japan to eastern North America caused an extreme genetic bottleneck with just two closely related clones detected throughout the introduced range. Both colonization events to North America involved host shifts to unrelated hemlock species. These results suggest that genetic diversity, host specialization and host phylogeny are not predictive of adelgid invasion. Monitoring non-native sentinel host trees and focusing on invasion pathways might be more effective methods of preventing invasion than making predictions using species traits or evolutionary history.

Effect of Antimicrobial Use in Agricultural Animals on Drug-resistant Foodborne Campylobacteriosis in Humans: A Systematic Literature Review.

Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant foodborne campylobacteriosis in humans. Based on publications from the United States (U.S.), Canada and Denmark from 2010 to July 2014, 195 articles were retained for abstract review, 50 met study criteria for full article review with 36 retained for which data are presented. Two publications reported increase in macrolide resistance of Campylobacter coli isolated from feces of swine receiving macrolides in feed, and one of these described similar findings for tetracyclines and fluoroquinolones. A study in growing turkeys demonstrated increased macrolide resistance associated with therapeutic dosing with Tylan® in drinking water. One publication linked tetracycline-resistant C. jejuni clone SA in raw cow's milk to a foodborne outbreak in humans. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Campylobacter from farm to fork. Recent literature confirms that on farm antibiotic selection pressure can increase colonization of animals with drug-resistant Campylobacter spp. but is inadequately detailed to establish a causal relationship between use of antimicrobials in agricultural animals and prevalence of drug-resistant foodborne campylobacteriosis in humans.

Jello Shot Consumption among Underage Youths in the United States.

We sought, for the first time, to identify the extent of jello shot consumption among underage youth. We conducted a study among a national sample of 1,031 youth, aged 13 to 20, using a pre-recruited internet panel maintained by GfK Knowledge Networks to assess past 30-day consumption of jello shots. Nearly one-fifth of underage youth have consumed jello shots in the past 30 days and jello shots make up an average of nearly 20% of their overall alcohol intake. Jello shot users in our sample were approximately 1.5 times more likely to binge drink, consumed approximately 1.6 times as many drinks per month, and were 1.7 times more likely to have been in a physical fight related to their alcohol use as drinkers in general. Ascertainment of jello shot use should become a standard part of youth alcohol surveillance and states should consider banning the sale of these products.

New statin use, mortality, and first cardiovascular events in older US Veterans by frailty status.

BACKGROUND: Statins are part of long-term medical regimens for many older adults. Whether frailty modifies the protective relationship between statins, mortality, and major adverse cardiovascular events (MACE) is unknown. METHODS: This was a retrospective study of US Veterans ≥65, without CVD or prior statin use seen in 2002-2012, followed through 2017. A 31-item frailty index was used. The co-primary endpoint was all-cause mortality or MACE (MI, stroke/TIA, revascularization, or cardiovascular death). Cox proportional hazards models were developed to evaluate the association of statin use with outcomes; propensity score overlap weighting accounted for confounding by indication. RESULTS: We identified 710,313 Veterans (mean age (SD) 75.3(6.5), 98% male, 89% white); 86,327 (12.1%) were frail. Over mean follow-up of 8 (5) years, there were 48.6 and 72.6 deaths per 1000 person-years (PY) among non-frail statin-users vs nonusers (weighted Incidence Rate Difference (wIRD)/1000 person years (PY), -24.0[95% CI, -24.5 to -23.6]), and 90.4 and 130.4 deaths per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -40.0[95% CI, -41.8 to -38.2]). There were 51.7 and 60.8 MACE per 1000PY among non-frail statin-users vs nonusers (wIRD/1000PY, -9.1[95% CI, -9.7 to -8.5]), and 88.2 and 102.0 MACE per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -13.8[95% CI, -16.2 to -11.4]). There were no significant interactions by frailty for statin users vs non-users by either mortality or MACE outcomes, p-interaction 0.770 and 0.319, respectively. Statin use was associated with lower risk of all-cause mortality (HR, 0.61 (0.60-0.61)) and MACE (HR 0.86 (0.85-0.87)). CONCLUSIONS: New statin use is associated with a lower risk of mortality and MACE, independent of frailty. These findings should be confirmed in a randomized clinical trial.

Species-specific profiles of per- and polyfluoroalkyl substances (PFAS) in small coastal sharks along the South Atlantic Bight of the United States.

Per- and polyfluoroalkyl substances (PFAS) have gained widespread commercial use across the globe in various industrial and consumer products, such as textiles, firefighting foams, and surface coating materials. Studies have shown that PFAS exhibit a strong tendency to accumulate within aquatic food webs, primarily due to their high bioaccumulation potential and resistance to degradation. Despite such concerns, their impact on marine predators like sharks remains underexplored. This study aimed to investigate the presence of 34 PFAS in the plasma (n = 315) of four small coastal sharks inhabiting the South Atlantic Bight of the United States (U.S). Among the sharks studied, bonnetheads (Sphyrna tiburo) had the highest ∑PFAS concentration (3031 ± 1674 pg g - 1 plasma, n = 103), followed by the Atlantic sharpnose shark (Rhizoprionodon terraenovae, 2407 ± 969 pg g - 1, n = 101), blacknose shark (Carcharhinus acronotus, 1713 ± 662 pg g - 1, n = 83) and finetooth shark (Carcharhinus isodon, 1431 ± 891 pg g - 1, n = 28). Despite declines in the manufacturing of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), the long-chain (C8 - C13) perfluoroalkyl acids (PFAAs) were frequently detected, with PFOS, perfluorodecanoic acid (PFDA), and perfluorotridecanoic acid (PFTrDA) present as the most dominant PFAS. Furthermore, males exhibited significantly higher ∑PFAS concentrations than females in bonnetheads (p < 0.01), suggesting possible sex-specific PFAS accumulation or maternal offloading in some species. The results of this study underscore the urgency for more extensive biomonitoring of PFAS in aquatic/marine environments to obtain a comprehensive understanding of the impact and fate of these emerging pollutants on marine fauna.

Centralized Interactive Phenomics Resource: an integrated online phenomics knowledgebase for health data users.

OBJECTIVE: Development of clinical phenotypes from electronic health records (EHRs) can be resource intensive. Several phenotype libraries have been created to facilitate reuse of definitions. However, these platforms vary in target audience and utility. We describe the development of the Centralized Interactive Phenomics Resource (CIPHER) knowledgebase, a comprehensive public-facing phenotype library, which aims to facilitate clinical and health services research. MATERIALS AND METHODS: The platform was designed to collect and catalog EHR-based computable phenotype algorithms from any healthcare system, scale metadata management, facilitate phenotype discovery, and allow for integration of tools and user workflows. Phenomics experts were engaged in the development and testing of the site. RESULTS: The knowledgebase stores phenotype metadata using the CIPHER standard, and definitions are accessible through complex searching. Phenotypes are contributed to the knowledgebase via webform, allowing metadata validation. Data visualization tools linking to the knowledgebase enhance user interaction with content and accelerate phenotype development. DISCUSSION: The CIPHER knowledgebase was developed in the largest healthcare system in the United States and piloted with external partners. The design of the CIPHER website supports a variety of front-end tools and features to facilitate phenotype development and reuse. Health data users are encouraged to contribute their algorithms to the knowledgebase for wider dissemination to the research community, and to use the platform as a springboard for phenotyping. CONCLUSION: CIPHER is a public resource for all health data users available at https://phenomics.va.ornl.gov/ which facilitates phenotype reuse, development, and dissemination of phenotyping knowledge.

Development of a nanoparticle-based influenza vaccine using the PRINT technology.

Historically it is known that presentation of vaccine antigens in particulate form, for a wide range of pathogens, has clear advantages over the presentation of soluble antigen alone [J.C. Aguilar, E.G. Rodriguez, Vaccine adjuvants revisited. Vaccine 25 (2007) 3752-3762, M. Singh, D. O'Hagan, Advances in vaccine adjuvants. Nature Biotechnology 17 (1999) 1075-1081]. Herein we describe a novel particle-based approach, which independently controls size, shape, and composition to control the delivery and presentation of vaccine antigen to the immune system. Highly uniform particles were produced using a particle molding technology called PRINT (Particle Replication in Non-wetting Templates) which is an off-shoot of imprint lithography [J Am Chem Soc 127 (2005) 10096-10100, J Am Chem Soc 126 (2004) 2322-2323, Chem Soc Rev 35 (2006) 1095-1104, J Am Chem Soc 130 (2008) 5008-5009, J Am Chem Soc 130 (2008) 5438-5439, Polymer Reviews 47 (2007) 321-327, Acc Chem Res 41 (2008) 1685-1695, Acc Chem Res 44 (10) (2011) 990-998]. Cylindrical (diameter [d]=80 nm, height [h]=320 nm) poly (lactide-co-glycolide) (PLGA) based PRINT particles were designed to electrostatically bind commercial trivalent injectable influenza vaccine. In a variety of blended PLGA formulations, these particles were safe and showed enhanced responses to influenza hemagglutinin in murine models. FROM THE CLINICAL EDITOR: Shape is one of the determining factors in interactions of nanoparticles with their biologic environment. PRINT technology is able to fabricate nearly uniform nanoparticles and this technology is tested here in murine models to effectively deliver influenza vaccine.

Framework of the Centralized Interactive Phenomics Resource (CIPHER) standard for electronic health data-based phenomics knowledgebase.

The development of phenotypes using electronic health records is a resource-intensive process. Therefore, the cataloging of phenotype algorithm metadata for reuse is critical to accelerate clinical research. The Department of Veterans Affairs (VA) has developed a standard for phenotype metadata collection which is currently used in the VA phenomics knowledgebase library, CIPHER (Centralized Interactive Phenomics Resource), to capture over 5000 phenotypes. The CIPHER standard improves upon existing phenotype library metadata collection by capturing the context of algorithm development, phenotyping method used, and approach to validation. While the standard was iteratively developed with VA phenomics experts, it is applicable to the capture of phenotypes across healthcare systems. We describe the framework of the CIPHER standard for phenotype metadata collection, the rationale for its development, and its current application to the largest healthcare system in the United States.

Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program.

Importance: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation. Objective: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population. Design, Setting, and Participants: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023. Exposures: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status. Main Outcomes and Measures: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events. Results: A total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%). Conclusions and Relevance: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.