Mendelian Randomization Study of ACLY and Cardiovascular Disease.

BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).

Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes.

BACKGROUND: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown. METHODS: We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes. RESULTS: Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes. CONCLUSIONS: In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.).

The Sapphire (0001) Surface: A Transparent and Ultraflat Substrate for DNA Nanostructure Imaging.

Mica is the current substrate of choice for DNA nanostructure imaging, mainly due to its atomically flat surface. However, these mica substrates are often not optically clear. In this work, sapphire has been evaluated as an alternative substrate, with potential to enable parallel optical and AFM studies. Well known for its thermal and chemical properties, sapphire is a hard ionic material with excellent optical properties. Because sapphire lacks the excellent basal cleavage properties of the sheet silicate mica, a process to anneal it at high temperature in water vapor was developed to achieve near atomically smooth (average roughness = 0.141 nm) terraces. AFM imaging was used to determine the dimensions of these terraces and to characterize the morphology of the DNA nanostructures, revealing that their structures were preserved, indicating that annealed c-plane cut (0001) sapphire is a promising substitute for mica as a flat and transparent substrate for DNA nanostructure studies.

Origami Arrays as Substrates for the Determination of Reaction Kinetics Using High-Speed Atomic Force Microscopy.

DNA nanostructures (DN) are powerful platforms for the programmable assembly of nanomaterials. As applications for DN both as a structural material and as a support for functional biomolecular sensing systems develop, methods enabling the determination of reaction kinetics in real time become increasingly important. In this report, we present a study of the kinetics of streptavidin binding onto biotinylated DN constructs enabled by these planar structures. High-speed AFM was employed at a 2.5 frame/s rate to evaluate the kinetics and indicates that the binding fully saturates in less than 60 s. When the the data was fitted with an adsorption-limited kinetic model, a forward rate constant of 5.03 × 105 s-1 was found.

Potential effects of reclassifying CKD as a coronary heart disease risk equivalent in the US population.

BACKGROUND: Persons with chronic kidney disease (CKD) are at high risk for cardiovascular disease events, but are not classified as such in current US cholesterol treatment guidelines. We examined potential effects of modified guidelines in which CKD was considered a "coronary heart disease (CHD) risk equivalent" for risk stratification. STUDY DESIGN: Nationally representative cross-sectional study. SETTING & PARTICIPANTS: 4,823 adults 20 years or older from the 2007-2010 National Health and Nutrition Examination Survey. PREDICTORS: Cardiovascular risk stratification based on current US cholesterol treatment guidelines and 2 simulated scenarios in which CKD stages 3-5 or CKD stages 1-5 were considered a CHD risk equivalent. OUTCOMES & MEASUREMENTS: Proportion of persons with low-density lipoprotein (LDL) cholesterol at levels above treatment targets and above the threshold for lipid-lowering therapy initiation, based on current guidelines and the 2 simulated scenarios. RESULTS: Under current guidelines, 55.1 million adults in 2010 did not achieve the target LDL cholesterol goal. Of these, 25.2 million had sufficiently elevated levels to meet recommendations for initiating lipid-lowering therapy; 12.1 million were receiving this therapy but remained above goal. When CKD stages 3-5 were considered a CHD risk equivalent, 59.2 million persons were above target LDL cholesterol goals, with 28.5 million and 13.3 million meriting therapy initiation and intensification, respectively. When CKD stages 1-5 were considered a CHD risk equivalent, 65.2 million adults were above goal, with 33.9 million and 14.4 million meriting therapy initiation and intensification, respectively. LIMITATIONS: CKD and LDL cholesterol defined using a single laboratory value. CONCLUSIONS: Many adults in the United States currently do not meet recommended goals for LDL cholesterol levels. Modifying the current cholesterol guidelines to include CKD as a CHD risk equivalent would lead to a substantial increase in both the number of persons with levels above LDL cholesterol treatment targets and those recommended to initiate lipid-lowering therapy.

Fluorescence shadow imaging of Hypsibius exemplaris reveals morphological differences between sucrose- and CaCl2-induced osmobiotes.

Tardigrades are renowned for their ability to survive a wide array of environmental stressors. In particular, tardigrades can curl in on themselves while losing a significant proportion of their internal water content to form a structure referred to as a tun. In surviving varying conditions, tardigrades undergo distinct morphological transformations that could indicate different mechanisms of stress sensing and tolerance specific to the stress condition. Methods to effectively distinguish between morphological transformations, including between tuns induced by different stress conditions, are lacking. Herein, an approach for discriminating between tardigrade morphological states is developed and utilized to compare sucrose- and CaCl2-induced tuns, using the model species Hypsibius exemplaris. A novel approach of shadow imaging with confocal laser scanning microscopy enabled production of three-dimensional renderings of Hys. exemplaris in various physiological states resulting in volume measurements. Combining these measurements with qualitative morphological analysis using scanning electron microscopy revealed that sucrose- and CaCl2-induced tuns have distinct morphologies, including differences in the amount of water expelled during tun formation. Further, varying the concentration of the applied stressor did not affect the amount of water lost, pointing towards water expulsion by Hys. exemplaris being a controlled process that is adapted to the specific stressors.

Cardiovascular risk factor burden, treatment, and control among adults with chronic kidney disease in the United States.

BACKGROUND: Cardiovascular disease is a major concern in persons with chronic kidney disease (CKD). We assessed the current burden of cardiovascular risk factors and differences in risk factor treatment and control in the general US adult population by CKD status. METHODS: A cross-sectional study of 10,741 adults aged 20+ years from the 2007-2010 National Health and Nutrition Examination Survey was performed. Persons were categorized into 3 groups: CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), CKD stages 1 and 2 (urinary albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate ≥60 mL/min/1.73 m(2)), and no CKD. RESULTS: The majority of adults with CKD stages 3 to 5 (79.8%) and stages 1 and 2 (59.1%) had ≥2 cardiovascular risk factors, substantially higher than adults without CKD (32.7%, P < .001). Diabetes was the most strongly associated risk factor and was highly specific for CKD stages 1 and 2 (prevalence ratio 2.53, 95% CI 2.21-2.89) and, to a lesser extent, CKD stages 3 to 5 (prevalence ratio 1.59, 95% CI 1.38-1.84). Most adults with diagnosed risk factors reported medication use for risk factor control, and pharmacologic treatment was more common among those with than without CKD. However, poor risk factor control was also common among persons treated for risk factors with CKD compared with those without CKD. CONCLUSIONS: There continues to be a substantial cardiovascular risk factor burden among adults with CKD stages 3 to 5 and, to a lesser extent, adults with CKD stages 1 and 2 when compared with adults without CKD. Overall, optimal risk factor control is low in adults with CKD, highlighting the need for aggressive cardiovascular risk reduction in adults with CKD.

The importance of low-density lipoprotein cholesterol measurement and control as performance measures: A joint clinical perspective from the National Lipid Association and the American Society for Preventive Cardiology.

Despite the established role of low-density lipoprotein cholesterol (LDL-C) as a major risk factor for cardiovascular disease (CVD), and the persistence of CVD as the leading cause of morbidity and mortality in the United States, national quality assurance metrics no longer include LDL-C measurement as a required performance metric. This clinical perspective reviews the history of LDL-C as a quality and performance metric and the events that led to its replacement. It also presents patient, healthcare provider, and health system rationales for re-establishing LDL-C measurement as a performance measure to improve cholesterol control in high-risk groups and to stem the rising tide of CVD morbidity and mortality, cardiovascular care disparities, and related healthcare costs.

The importance of low-density lipoprotein cholesterol measurement and control as performance measures: A joint Clinical Perspective from the National Lipid Association and the American Society for Preventive Cardiology.

Despite the established role of low-density lipoprotein cholesterol (LDL-C) as a major risk factor for cardiovascular disease (CVD), and the persistence of CVD as the leading cause of morbidity and mortality in the United States, national quality assurance metrics no longer include LDL-C measurement as a required performance metric. This clinical perspective reviews the history of LDL-C as a quality and performance metric and the events that led to its replacement. It also presents patient, healthcare provider, and health system rationales for re-establishing LDL-C measurement as a performance measure to improve cholesterol control in high-risk groups and to stem the rising tide of CVD morbidity and mortality, cardiovascular care disparities, and related healthcare costs.

Graphene surface-enabled lithium ion-exchanging cells: next-generation high-power energy storage devices.

Herein reported is a fundamentally new strategy for the design of high-power and high energy-density devices. This approach is based on the exchange of lithium ions between the surfaces (not the bulk) of two nanostructured electrodes, completely obviating the need for lithium intercalation or deintercalation. In both electrodes, massive graphene surfaces in direct contact with liquid electrolyte are capable of rapidly and reversibly capturing lithium ions through surface adsorption and/or surface redox reaction. These devices, based on unoptimized materials and configuration, are already capable of storing an energy density of 160 Wh/kg(cell), which is 30 times higher than that (5 Wh/kg(cell)) of conventional symmetric supercapacitors and comparable to that of Li-ion batteries. They are also capable of delivering a power density of 100 kW/kg(cell), which is 10 times higher than that (10 kW/kg(cell)) of supercapacitors and 100 times higher than that (1 kW/kg(cell)) of Li-ion batteries.

Bayesian network analysis of panomic biological big data identifies the importance of triglyceride-rich LDL in atherosclerosis development.

Introduction: We sought to explore biomarkers of coronary atherosclerosis in an unbiased fashion. Methods: We analyzed 665 patients (mean ± SD age, 56 ± 11 years; 47% male) from the GLOBAL clinical study (NCT01738828). Cases were defined by the presence of any discernable atherosclerotic plaque based on comprehensive cardiac computed tomography (CT). De novo Bayesian networks built out of 37,000 molecular measurements and 99 conventional biomarkers per patient examined the potential causality of specific biomarkers. Results: Most highly ranked biomarkers by gradient boosting were interleukin-6, symmetric dimethylarginine, LDL-triglycerides [LDL-TG], apolipoprotein B48, palmitoleic acid, small dense LDL, alkaline phosphatase, and asymmetric dimethylarginine. In Bayesian analysis, LDL-TG was directly linked to atherosclerosis in over 95% of the ensembles. Genetic variants in the genomic region encoding hepatic lipase (LIPC) were associated with LIPC gene expression, LDL-TG levels and with atherosclerosis. Discussion: Triglyceride-rich LDL particles, which can now be routinely measured with a direct homogenous assay, may play an important role in atherosclerosis development. Clinical trial registration: GLOBAL clinical study (Genetic Loci and the Burden of Atherosclerotic Lesions); [https://clinicaltrials.gov/ct2/show/NCT01738828?term=NCT01738828&rank=1], identifier [NCT01738828].

Graphene-based supercapacitor with an ultrahigh energy density.

A supercapacitor with graphene-based electrodes was found to exhibit a specific energy density of 85.6 Wh/kg at room temperature and 136 Wh/kg at 80 °C (all based on the total electrode weight), measured at a current density of 1 A/g. These energy density values are comparable to that of the Ni metal hydride battery, but the supercapacitor can be charged or discharged in seconds or minutes. The key to success was the ability to make full utilization of the highest intrinsic surface capacitance and specific surface area of single-layer graphene by preparing curved graphene sheets that will not restack face-to-face. The curved morphology enables the formation of mesopores accessible to and wettable by environmentally benign ionic liquids capable of operating at a voltage >4 V.

Detecting substrate engagement: responses of tarsal campaniform sensilla in cockroaches.

Sensory signals of contact and engagement with the substrate are important in the control and adaptation of posture and locomotion. We characterized responses of campaniform sensilla, receptors that encode forces as cuticular strains, in the tarsi (feet) of cockroaches using neurophysiological techniques and digital imaging. A campaniform sensillum on the fourth tarsal segment was readily identified by its large action potential in nerve recordings. The receptor discharged to contractions of the retractor unguis muscle, which engages the pretarsus (claws and arolium) with the substrate. We mimicked the effects of muscle contractions by applying displacements to the retractor apodeme (tendon). Sensillum firing did not occur to unopposed movements, but followed engagement of the claws with an object. Vector analysis of forces suggested that resisted muscle contractions produce counterforces that axially compress the tarsal segments. Close joint packing of tarsal segments was clearly observed following claw engagement. Physiological experiments showed that the sensillum responded vigorously to axial forces applied directly to the distal tarsus. Discharges of tarsal campaniform sensilla could effectively signal active substrate engagement when the pretarsal claws and arolium are used to grip the substrate in climbing, traversing irregular terrains or walking on inverted surfaces.

NTA directed protein nanopatterning on DNA Origami nanoconstructs.

Precisely patterning proteins and other molecules at the nanoscale is crucial to future biosensing and optoelectronic applications. One- and two-dimensional DNA nanoconstructs have proven to be useful scaffolds for nanopatterning. This paper demonstrates the application of nitrilotriacetic acid (NTA) forming chelate complexes to localize histidine (His) tagged proteins via Ni(2+) ions onto DNA based structures. Particularly, enhanced green fluorescent protein (EGFP) was directed to specific surface locations on a designed DNA Origami nanoconstruct, and the resulting EGFP nanopattern was visualized using atomic force microscopy (AFM).

Aggregation Patterns of Sensory Sensillae in the Food Canal and Cibarium of Haematobia irritans (Diptera: Muscidae).

Although mean body lengths of females were significantly greater than males in individuals drawn from two Haematobia irritans (L.) sample populations (n = 20 females and n = 20 males from West Virginia; n = 20 females and n = 20 males from Georgia), there were no significant differences in food canal lengths for females versus males at either site. Variable numbers (21-37) of setiform sensillae occurred throughout the length of the food canal, but such sensillae were significantly aggregated in the distal-most canal region of both sexes at both sites. There was no significant difference in mean numbers of food canal setiform sensillae between females and males. Four basiconic (campaniform) sensillae were consistently observed in the food canal of every fly; always aggregated in the distal-most canal region. Setiform sensillae in the cibarium also varied in number (6-13), but were significantly aggregated in the median and proximal cibarial regions. Four (occasionally three) peg-like basiconic sensillae were also observed in the cibarium of sample individuals; always in the distal and distal median regions of both sexes. Sensory sensillae (both setiform and basiconic) in both the food canal and cibarium were similarly aggregated for both sexes at both sites. Aggregation of setiform and basiconic sensillae in the food canal suggests that the distal canal region is most critical for sensory input regarding monitoring blood flow, and stress forces brought to bear on the cuticle as the labrum tip penetrates the host's skin.

Operationalizing a Data to Care Strategy in Michigan Through Cross-Agency Collaborations.

BACKGROUND: For persons with HIV infection (PWH), viral load suppression is essential to maintaining health and reducing the likelihood of HIV transmission. Data to Care (D2C) is an important strategy for improving HIV outcomes but may be resource-intensive to execute. SETTING: In 2016, Michigan joined the HIV Health Improvement Affinity Group to strengthen D2C partnerships between its Medicaid and HIV program. Goals included establishing routine data sharing, matching data sources to understand health outcomes, and collaborating to turn data into action. METHODS: Michigan established data use agreements to assess gaps in care for PWH enrolled in Medicaid. The HIV Surveillance Program used Link Plus to match surveillance records on PWH to Medicaid's active beneficiary file to identify PWH who were beneficiaries as of December 31, 2015. RESULTS: Matching the 2,300,877 Michigan Medicaid beneficiaries with the 15,845 PWH in HIV surveillance yielded 4822 matched PWH enrolled in Medicaid in 2015. Of Medicaid beneficiaries with HIV, 597 had no evidence of receiving HIV care, representing 20% of all Michigan residents with HIV and not in care in 2015. CONCLUSION: D2C is an effective strategy for improving HIV care continuum outcomes but can be relatively inefficient if implementation models rely solely on public health infrastructure. Through the HIV Health Improvement Affinity Group, Michigan's Medicaid and HIV programs leveraged their combined data assets to evaluate and improve care quality and outcomes for PWH on Medicaid. Partnerships between Medicaid and public health offer attractive mechanisms for potentially increasing efficiency and effectiveness of D2C investments.

Effects of force detecting sense organs on muscle synergies are correlated with their response properties.

Sense organs that monitor forces in legs can contribute to activation of muscles as synergist groups. Previous studies in cockroaches and stick insects showed that campaniform sensilla, receptors that encode forces via exoskeletal strains, enhance muscle synergies in substrate grip. However synergist activation was mediated by different groups of receptors in cockroaches (trochanteral sensilla) and stick insects (femoral sensilla). The factors underlying the differential effects are unclear as the responses of femoral campaniform sensilla have not previously been characterized. The present study characterized the structure and response properties (via extracellular recording) of the femoral sensilla in both insects. The cockroach trochantero-femoral (TrF) joint is mobile and the joint membrane acts as an elastic antagonist to the reductor muscle. Cockroach femoral campaniform sensilla show weak discharges to forces in the coxo-trochanteral (CTr) joint plane (in which forces are generated by coxal muscles) but instead encode forces directed posteriorly (TrF joint plane). In stick insects, the TrF joint is fused and femoral campaniform sensilla discharge both to forces directed posteriorly and forces in the CTr joint plane. These findings support the idea that receptors that enhance synergies encode forces in the plane of action of leg muscles used in support and propulsion.

Age-related dystrophin-glycoprotein complex structure and function in the rat extensor digitorum longus and soleus muscle.

This study tested the hypothesis that age-related changes in the dystrophin-glycoprotein complex (DGC) may precede age-associated alterations in muscle morphology and function. Compared to those in adult (6 month) rats, extensor digitorum longus (EDL) and soleus muscle mass was decreased in old (30 month) and very old (36 month) Fischer 344/NNiaHSD x Brown Norway/BiNia rats. The amount of dystrophin, beta-dystroglycan, and alpha-sarcoglycan increased with aging in the EDL and decreased with aging in the soleus. alpha-Dystroglycan levels were increased with aging in both muscles and displayed evidence of altered glycosylation. Immunostaining for the presence of antibody infiltration and dystrophin following increased muscle stretch suggested that the aging in the soleus was characterized by diminished membrane integrity. Together, these data suggest that aging is associated with alterations in EDL and soleus DGC protein content and localization. These results may implicate the DGC as playing a role in age-associated skeletal muscle remodeling.

DNA Origami Reorganizes upon Interaction with Graphite: Implications for High-Resolution DNA Directed Protein Patterning.

Although there is a long history of the study of the interaction of DNA with carbon surfaces, limited information exists regarding the interaction of complex DNA-based nanostructures with the important material graphite, which is closely related to graphene. In view of the capacity of DNA to direct the assembly of proteins and optical and electronic nanoparticles, the potential for combining DNA-based materials with graphite, which is an ultra-flat, conductive carbon substrate, requires evaluation. A series of imaging studies utilizing Atomic Force Microscopy has been applied in order to provide a unified picture of this important interaction of structured DNA and graphite. For the test structure examined, we observe a rapid destabilization of the complex DNA origami structure, consistent with a strong interaction of single-stranded DNA with the carbon surface. This destabilizing interaction can be obscured by an intentional or unintentional primary intervening layer of single-stranded DNA. Because the interaction of origami with graphite is not completely dissociative, and because the frustrated, expanded structure is relatively stable over time in solution, it is demonstrated that organized structures of pairs of the model protein streptavidin can be produced on carbon surfaces using DNA origami as the directing material.

Changing characteristics of statin-related cIMT trials from 1988 to 2006.

OBJECTIVES: Changes in cIMT have not been consistently correlated with cardiovascular risk reduction in clinical studies. The variability of carotid intima media thickness (cIMT) changes in published statin LDL-C-lowering studies in relation to various baseline and study characteristics was assessed. METHODS: This was an exploratory analysis of study-level data pooled from statin-treatment arms of 13 studies conducted during 1988-2006. Baseline mean common carotid artery (CCA)/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Potential relationships between prespecified covariates and cIMT changes were assessed. RESULTS: Baseline mean CCA/cIMT and LDL-C levels were higher in the combined studies conducted before year 2000 (0.8521 mm) than after 2000 (0.7458 mm), and somewhat higher in study populations of patients with coronary heart disease risk and those with greater LDL-C reductions. Mean CCA/cIMT changes were also larger for the studies conducted before 2000 (-0.0119 mm/year) than after 2000 (-0.0013 mm/year). Notably, studies conducted before 2000 were of longer duration (≥ 2 years) than after 2000 (<2 years). Heterogeneity in cIMT change was attributed to baseline and study-design characteristics. Longer study duration and greater LDL-C reductions were significantly related to larger annualized cIMT changes. Maximum cIMT results were similar. CONCLUSION: Baseline cIMT and LDL-C levels were lower, and cIMT changes were smaller in statin cIMT trials conducted after 2000 than those before 2000. These trends are consistent with increased treatment and control of high LDL-C levels over recent years in clinical practice, and may influence the results of cIMT studies.