Poisson-Schroedinger-Continuity two-dimensional analysis of both short (ballistic) and long (drift-diffusion) III-V FETs

It was recently shown that the quantum mechanical results of the Landauer theory of conduction, applied to a simple one-layer channel FET, can be recast in the traditional drift-diffusion form but with the mobility and injection velocity redefined in a new context. Based on that, we have performed two-dimensional Poisson-Schrödinger-Continuity calculations for both long drift-diffusion and short ballistic quantum well FETs. Very good agreement with many-layer, state-of-the-art InGaAs devices has been achieved provided that only one parameter, the saturation velocity υsat of the mobility function, is rescaled so that our calculated drain current agrees with the experimental value at very large gate voltages VG. This single value of υsat has been used at all other VG. Our calculations are not only a test of the equivalence described above but valuable information about the sub-threshold regime and especially the leakage currents is obtained. This information is usually absent in rigorous Landauer-type - or equivalently non-equilibrium Green's functions - calculations which are performed in simplified FET systems

Ceramide remodeling and risk of cardiovascular events and mortality

BackgroundRecent studies suggest that circulating concentrations of specific ceramide species may be associated with coronary risk and mortality. We sought to determine the relations between the most abundant plasma ceramide species of differing acyl chain lengths and the risk of coronary heart disease (CHD) and mortality in community‐based samples. Methods and ResultsWe developed a liquid chromatography/mass spectrometry assay to quantify plasma C24:0, C22:0, and C16:0 ceramides and ratios of these very–long‐chain/long‐chain ceramides in 2642 FHS (Framingham Heart Study) participants and in 3134 SHIP (Study of Health in Pomerania) participants. Over a mean follow‐up of 6 years in FHS, there were 88 CHD and 90 heart failure (HF) events and 239 deaths. Over a median follow‐up time in SHIP of 5.75 years for CHD and HF and 8.24 years for mortality, there were 209 CHD and 146 HF events and 377 deaths. In meta‐analysis of the 2 cohorts and adjusting for standard CHD risk factors, C24:0/C16:0 ceramide ratios were inversely associated with incident CHD (hazard ratio per average SD increment, 0.79; 95% confidence interval, 0.71–0.89; P<0.0001) and inversely associated with incident HF (hazard ratio, 0.78; 95% confidence interval, 0.61–1.00; P=0.046). Moreover, the C24:0/C16:0 and C22:0/C16:0 ceramide ratios were inversely associated with all‐cause mortality (C24:0/C16:0: hazard ratio, 0.60; 95% confidence interval, 0.56–0.65; P<0.0001; C22:0/C16:0: hazard ratio, 0.65; 95% confidence interval, 0.60–0.70; P<0.0001). ConclusionsThe ratio of C24:0/C16:0 ceramides in blood may be a valuable new biomarker of CHD risk, HF risk, and all‐cause mortality in the community

Association of subclinical atherosclerosis with echocardiographic indices of cardiac remodeling: The Framingham Study

BACKGROUND: It is well established that coronary artery disease progresses along with myocardial disease. However, data on the association between coronary artery calcium (CAC) and echocardiographic variables are lacking. METHODS AND RESULTS: Among 2,650 Framingham Study participants (mean age 51 yrs, 48% women; 40% with CAC \u3e 0), we related CT-based CAC score to left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), E/e\u27, global longitudinal strain (GLS), left atrial emptying fraction (LAEF), and aortic root diameter (AoR), using multivariable-adjusted generalized linear models. CAC score (independent variable) was used as log-transformed continuous [ln(CAC+1)] and as a categorical (0, 1-100, and \u3e /=101) variable. Adjusting for standard risk factors, higher CAC score was associated with higher LVMi and AoR (betaLVMI per 1-SD increase 0.012, betaAoR 0.008; P \u3c 0.05, for both). Participants with 1 \u3c /=CAC \u3c /=100 and those with CAC \u3e /=101 had higher AoR (betaAoR 0.013 and 0.020, respectively, P = 0.01) than those with CAC = 0. CAC score was not significantly associated with LVEF, E/e\u27, GLS or LAEF. Age modified the association of CAC score with AoR; higher CAC scores were associated with larger AoR more strongly in older ( \u3e 58 years; betaAoR0.0042;P \u3c 0.007) than in younger ( \u3c /=58 years) participants (betaAoR0.0027;P \u3c 0.03). CONCLUSIONS: We observed that subclinical atherosclerosis was associated with ventricular and aortic remodeling. The prognostic significance of these associations warrants evaluation in additional mechanistic studies

Clinical correlates of plasma insulin levels over the life course and association with incident type 2 diabetes: the Framingham Heart Study

Introduction Insulin is a glucose-lowering hormone that affects carbohydrate, lipid, and protein metabolism. Limited data exist on the correlates of insulin levels over the life course in healthy community-dwelling individuals. Research design and methods Using multilevel modeling of multiple serial observations over 21 years, we assessed the longitudinal correlates of fasting insulin and the cross-sectional correlates of fasting and 2-hour (2h, post 75 g glucose challenge) plasma insulin concentrations in 2140 relatively healthy Framingham Heart Study participants without diabetes (61% women; mean age, 42 years). We used multivariable-adjusted Cox regression to relate glycemic markers (fasting and 2h-insulin, fasting glucose, 2h-glucose, and hemoglobin A1C) to the risk of type 2 diabetes during follow-up. Results Over the life course, fasting insulin concentrations were inversely associated with age, male sex, and physical activity, whereas waist circumference, the total/high-density lipoprotein (HDL) cholesterol ratio, and blood triglycerides were positively associated with insulin levels (p<0.005 for all). Male sex (inversely related) and the total/HDL cholesterol ratio (positively related) emerged as the most important cross-sectional correlates of 2h-insulin (p<0.005 for all). All markers were associated with higher risk of type 2 diabetes (352 cases, median follow-up 18 years, p<0.001 for all). Conclusions We observed common and distinct correlates of fasting and 2h-insulin levels. Our findings highlight a potential role of insulin in lipid and lipoprotein metabolism. Furthermore, fasting and 2h-insulin are critical markers of future diabetes risk. Further studies are needed to confirm our findings

Association of circulating ceramides with cardiac structure and function in the community: The Framingham Heart Study

Background A higher circulating plasma ceramide ratio (C16:0/C24:0) is associated with an increased risk of heart failure, even after accounting for standard risk factors including lipid markers. However, the pathobiological mechanisms that underlie this association are incompletely understood. We tested the hypothesis that plasma ceramide ratio (C16:0/C24:0) is associated with adverse cardiac remodeling in the community. Methods and Results We evaluated 2652 Framingham Offspring Study participants (mean age, 66±9 years; 55% women) who attended their eighth examination cycle and underwent routine echocardiography and liquid chromatography-tandem mass spectrometry-based assays for circulating ceramide concentrations. We used multivariable linear regression models to relate C16:0/C24:0 (independent variable) to the following echocardiographic measures (dependent variables; separate models for each): left ventricular mass, left ventricular ejection fraction, left atrial emptying fraction, left atrial end-systolic volume, E/e\u27 (a measure of left ventricular diastolic function), and left ventricular global circumferential and longitudinal strain by speckle-tracking echocardiography. In multivariable-adjusted analyses, higher C16:0/C24:0 per standard deviation increment was associated with lower left ventricular ejection fraction (0.991-fold change in left ventricular ejection fraction

Left ventricular mass and incident chronic kidney disease

Chronic kidney disease (CKD) is associated with incident cardiovascular morbidity and mortality. Whether subclinical cardiovascular disease and target organ damage is associated with incident CKD is unknown. We investigated the relations of echocardiographic left ventricular mass (LVM) with incident CKD. We evaluated 2258 Framingham Offspring cohort participants (mean age, 57 years; 56% women) who underwent echocardiography at a routine examination and had an estimated glomerular filtration rate ≥60 mL/min per 1.73 m2. We used Cox proportional hazards regression with discrete time intervals to relate sex-standardized LVM (independent variable) to the incidence of CKD, defined as estimated glomerular filtration rate <60 L/min per 1.73 m2, on follow-up. During a median follow-up of 14.6 years, 373 (16.5%) participants developed incident CKD. Higher LVM was associated with higher risk of CKD after adjusting for prevalent cardiovascular disease, body mass index, systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, antihypertensive medication, smoking, and diabetes mellitus (hazard ratio, 1.15 [95% CI, 1.03-1.29]; P=0.017) per 1-SD increase in LVM g/m2. Further adjustment for baseline estimated glomerular filtration rate (adjusted hazard ratio, 1.16 [95% CI, 1.04-1.31]; P=0.010) and baseline urine albumin/creatinine ratio (adjusted hazard ratio, 1.18 [95% CI, 1.04-1.33]; P=0.009) slightly attenuated the association. In our community-based sample, LVM was associated with incident CKD prospectively, which suggests that the relations between CKD and subclinical cardiovascular disease may be bidirectional. Further studies are needed to confirm our findings

Associations of Circulating Dimethylarginines with the Metabolic Syndrome in the Framingham Offspring Study

BACKGROUND: Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively. METHODS: We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study who attended a routine examination. RESULTS: Adjusting for age, sex, smoking, and eGFR, we observed significant associations of ADMA (direct) and ARG/ADMA (inverse) with odds of MetS (N = 1461 prevalent cases; Odds Ratio [OR] per SD increment 1.13, 95%CI 1.04-1.22; and 0.89, 95%CI 0.82-0.97 for ADMA and ARG/ADMA, respectively). Upon further adjustment for waist circumference, systolic and diastolic blood pressure, glucose, high-density lipoprotein cholesterol, and triglycerides, we observed a positive relation between SDMA and MetS (OR per SD increment 1.15, 95% CI 1.01-1.30) but the other associations were rendered statistically non-significant. We did not observe statistically significant associations between any of the methylarginines and the risk of new-onset MetS (752 incident events) over a median follow-up of 11 years. CONCLUSION: It is unclear whether dimethylarginines play an important role in the incidence of cardiometabolic risk in the community, notwithstanding cross-sectional associations. Further studies of larger samples are needed to replicate our findings

Circulating ceramide ratios and risk of vascular brain aging and dementia

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer\u27s disease (AD) dementia in a large, community-based sample. METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56-0.96) and AD dementia (HR 0.73, 95% CI 0.53-1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57-0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53-1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (-0.05 ± 0.02, P = 0.02; -0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. CONCLUSIONS: Higher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults

Interrelations Between Arterial Stiffness, Target Organ Damage, and Cardiovascular Disease Outcomes

Background-Excess transmission of pressure pulsatility caused by increased arterial stiffness may incur microcirculatory damage in end organs (target organ damage [TOD]) and, in turn, elevate risk for cardiovascular disease (CVD) events.Methods and Results-We related arterial stiffness measures (carotid-femoral pulse wave velocity, mean arterial pressure, central pulse pressure) to the prevalence and incidence of TOD (defined as albuminuria and/or echocardiographic left ventricular hypertrophy) in up to 6203 Framingham Study participants (mean age 50 +/- 15 years, 54% women). We then related presence of TOD to incident CVD in multivariable Cox regression models without and with adjustment for arterial stiffness measures. Cross-sectionally, greater arterial stiffness was associated with a higher prevalence of TOD (adjusted odds ratios ranging from 1.23 to 1.54 per SD increment in arterial stiffness measure, P<0.01). Prospectively, increased carotid-femoral pulse wave velocity was associated with incident albuminuria (odds ratio per SD 1.28, 95% CI, 1.02-1.61; P<0.05), whereas higher mean arterial pressure and central pulse pressure were associated with incident left ventricular hypertrophy (odds ratio per SD 1.37 and 1.45, respectively; P<0.01). On follow-up, 297 of 5803 participants experienced a first CVD event. Presence of TOD was associated with a 33% greater hazard of incident CVD (95% CI, 0-77%; P<0.05), which was attenuated upon adjustment for baseline arterial stiffness measures by 5-21%.Conclusions-Elevated arterial stiffness is associated with presence of TOD and may partially mediate the relations of TOD with incident CVD. Our observations in a large community-based sample suggest that mitigating arterial stiffness may lower the burden of TOD and, in turn, clinical CVD

Association of Novel Biomarkers of Cardiovascular Stress With Left Ventricular Hypertrophy and Dysfunction: Implications for Screening

Background: Currently available screening tools for left ventricular (LV) hypertrophy (LVH) and systolic dysfunction (LVSD) are either expensive (echocardiography) or perform suboptimally (B‐type natriuretic peptide [BNP]). It is unknown whether newer biomarkers are associated with LVH and LVSD and can serve as screening tools. Methods and Results: We studied 2460 Framingham Study participants (mean age 58 years, 57% women) with measurements of biomarkers mirroring cardiac biomechanical stress (soluble ST‐2 [ST2], growth differentiation factor‐15 [GDF‐15] and high‐sensitivity troponin I [hsTnI]) and BNP. We defined LVH as LV mass/height2 ≥the sex‐specific 80th percentile and LVSD as mild/greater impairment of LV ejection fraction (LVEF) or a fractional shortening <0.29. Adjusting for standard risk factors in logistic models, BNP, GDF‐15, and hsTnI were associated with the composite echocardiographic outcome (LVH or LVSD), odds ratios (OR) per SD increment in log‐biomarker 1.29, 1.14, and 1.18 (95% CI: 1.15 to 1.44, 1.004 to 1.28, and 1.06 to 1.31), respectively. The C‐statistic for the composite outcome increased from 0.765 with risk factors to 0.770 adding BNP, to 0.774 adding novel biomarkers. The continuous Net Reclassification Improvement was 0.212 (95% CI: 0.119 to 0.305, P<0.0001) after adding the novel biomarkers to risk factors plus BNP. BNP was associated with LVH and LVSD in multivariable models, whereas GDF‐15 was associated with LVSD (OR 1.41, 95% CI: 1.16 to 1.70), and hsTnI with LVH (OR 1.22, 95% CI: 1.09 to 1.36). ST2 was not significantly associated with any outcome. Conclusions: Our community‐based investigation suggests that cardiac stress biomarkers are associated with LVH and LVSD but may have limited clinical utility as screening tools