Monolithic CMOS sensor platform featuring an array of 9'216 carbon-nanotube-sensor elements and low-noise, wide-bandwidth and wide-dynamic-range readout circuitry.

We present the design and characterization of a monolithic complementary metal-oxide-semiconductor (CMOS) biosensor platform comprising of a switch-matrix-based array of 9'216 carbon nanotube field-effect transistors (CNTFETs) and associated readout circuitry. The switch-matrix allows for flexible selection and simultaneous routing of 96 sensor elements to the corresponding readout channels. A low-noise, wide-bandwidth, wide-dynamic-range transimpedance continuous-time amplifier architecture has been implemented to facilitate resistance measurements in the range between 50 kΩ and 1 GΩ at a bandwidth of up to 1 MHz. The achieved accuracy of the resistance measurements over the whole range is 4%. The system has been successfully fabricated and tested and shows a noise performance equal to 2.14 pArms at a bandwidth of 1 kHz and 0.84 nArms at a bandwidth of 1 MHz. A batch integration of the CNTFETs has been achieved by using a dielectrophoresis (DEP)-based manipulation technique. The current-voltage curves of CNTFETs have been acquired, and the sensing capabilities of the system have been demonstrated by recording resistance changes of CNTFETs upon exposure to solutions with different pH values and different concentrations of NaCl. The smallest resolvable concentrations for the respective analytes were estimated to amount to 0.025 pH-units and 4 mM NaCl.

Carbon-Nanotube-Based Monolithic CMOS Platform for Electrochemical Detection of Neurotransmitter Glutamate.

We present a monolithic biosensor platform, based on carbon-nanotube field-effect transistors (CNTFETs), for the detection of the neurotransmitter glutamate. We used an array of 9'216 CNTFET devices with 96 integrated readout and amplification channels that was realized in complementary metal-oxide semiconductor technology (CMOS). The detection principle is based on amperometry, where electrochemically active hydrogen peroxide, a product of the enzymatic reaction of the target analyte and an enzyme that was covalently bonded to the CNTFET, modulated the conductance of the CNTFET-based sensors. We assessed the performance of the CNTs as enzymatic sensors by evaluating the minimal resolvable concentration change of glutamate in aqueous solutions. The minimal resolvable concentration change amounted to 10 µM of glutamate, which was one of the best values reported for CMOS-based systems so far.

Dyslipidemias in the prevention of cardiovascular disease: risks and causality.

Atherosclerotic cardiovascular disease is now the major global cause of death, despite reductions in CVD deaths in developed societies. Dyslipidemias are a major contributor, but the mass occurrence of CVD relates to the combined effects of hyperlipidemia, hypertension, and smoking. Total blood cholesterol and LDL-cholesterol relate to CVD risk in an independent and graded manner and fulfill the criteria for causality. Therapeutic reduction of these lipid fractions is associated with improved outcomes. There is good evidence that HDL-cholesterol, triglycerides, and Lp(a) relate to CVD although the evidence for a causal relationship is weaker. The HDL association with CVD is largely independent of other risk factors whereas triglycerides may be more important as signaling a need to look intensively for other measures of risk such as central obesity, hypertension, low HDL-cholesterol, and glucose intolerance. Lp(a) is an inherited risk marker. The benefit of lowering it is uncertain, but it may be that its impact on risk is attenuated if LDL-cholesterol is low.

Total cardiovascular disease risk assessment: a review.

PURPOSE OF REVIEW: The high risk strategy for the prevention of cardiovascular disease (CVD) requires an assessment of an individual's total CVD risk so that the most intensive risk factor management can be directed towards those at highest risk. Here we review developments in the assessment and estimation of total CVD risk. RECENT FINDINGS: Recent advances have focused on newer approaches to expressing risk, including lifetime risk and risk age; these are particularly useful in communicating risk to younger individuals. Additionally, increased emphasis has been placed on the role of body weight and abdominal obesity in CVD risk. Several recent large studies have clarified a number of issues relevant to the management of CVD risk, a matter of growing global concern. SUMMARY: Simple risk estimation systems utilizing only easily measured variables have a role in improving the accessibility and cost effectiveness of risk estimation. The addition of newer variables to risk estimation systems may be particularly useful for those at intermediate risk, in order to more correctly reclassify such individuals into appropriate risk categories.

Relationships between body mass index, cardiovascular mortality, and risk factors: a report from the SCORE investigators.

BACKGROUND: Although cardiovascular disease (CVD) is the biggest global cause of death, CVD mortality is falling in developed countries. There is concern that this trend may be offset by increasing levels of obesity. DESIGN: We used the Systematic Coronary Risk Evaluation (SCORE) data set to examine relationships between body mass index (BMI), conventional risk factors and CVD mortality. METHODS: The SCORE data set comprises data from 12 European cohort studies. The relationship between BMI and CVD mortality was examined in each BMI category using univariable and multivariable (Cox) analyses. The SCORE population was also divided into gender and age strata: under 40, 40-49, 50-59, and over 60. The rate of CVD mortality in each BMI category was calculated within each gender and age stratum. Relationships between BMI and other CVD risk factors were also examined. RESULTS: There was a strong, graded but J-shaped univariable relationship between BMI and CVD mortality in both genders. Each 5-unit increase in BMI was associated with an increase in CVD mortality of 34% in men and 29% in women. The hazard ratios remained significant when adjusted for age, self-reported smoking status, total cholesterol, and systolic blood pressure (SBP). On additional adjustment for diabetes and high-density lipoprotein cholesterol (HDL), the association between BMI and CVD mortality did not persist. In all age groups except those over 60 there were significant relationships between increased BMI and CVD mortality. In the over-60 age group the only significant relationships with mortality were in underweight and severely overweight women and mildly obese men. After adjustment for age, each 1-unit increase in BMI was associated with a 1.14 mmHg increase in SBP, 0.055 mmol/l increase in total cholesterol, and a 0.024 mmol/l decrease in HDL in men. Figures were slightly lower in women. CONCLUSIONS: Overall, overweight and obesity relate to CVD mortality in a strong and graded manner. The effects are greater in women and markedly so in younger persons. It is likely that a substantial part of the BMI-associated risk of CVD mortality is mediated through other known CVD risk factors. This increases the public health importance of BMI as both a simple indicator and mediator of CVD risk.

Simplifying cardiovascular risk estimation using resting heart rate.

AIMS: Elevated resting heart rate (RHR) is a known, independent cardiovascular (CV) risk factor, but is not included in risk estimation systems, including Systematic COronary Risk Evaluation (SCORE). We aimed to derive risk estimation systems including RHR as an extra variable and assess the value of this addition. METHODS AND RESULTS: The National FINRISK study (including 14,997 men and 15,861 women) was used to derive two formulas for estimation of 10 year risk of CV disease (CVD) mortality. The first formula contained current SCORE variables-total cholesterol, systolic blood pressure, smoking, age and gender. Inclusion of RHR resulted in only minor improvements in discrimination, based on both area under receiver operating characteristic curve (AUROC, men: 0.840 from 0.838, P = 0.5038; women: 0.87 from 0.865, P = 0.0522) and net reclassification index (NRI). The second, simplified formula contained only, age, smoking, gender, and body mass index. Addition of RHR to this simplified formula resulted in a statistically significant and meaningful improvement in AUROC (men: 0.819 from 0.812, P = 0.037; women: 0.862 from 0.827, P = 0.023) and NRI (0.05). Calibration also improved. A simple chart for estimating 10 year risk of fatal CVD including RHR is presented. CONCLUSION: Addition of RHR to formulas already containing lipid and blood pressure measures does not appreciably improve risk estimation. However, inclusion of RHR in simple systems, which can potentially enhance cost-effectiveness and accessibility of risk estimation, is useful.

Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women.

BACKGROUND: Elevated resting heart rate (RHR) is known to be associated with reduced survival but inconsistencies remain, including lack of significance in most studies of healthy women, lack of independence from systolic blood pressure (SBP) in some, and the suggestion that RHR is merely functioning as a marker of physical inactivity or other comorbidities. We aimed to clarify these inconsistencies. METHODS: We analyzed the effect of RHR on end points in the National FINRISK Study; a representative, prospective study using Cox proportional hazards model. Ten-thousand five-hundred nineteen men and 11,334 women were included, excluding those with preexisting coronary heart disease, angina, heart failure, or on antihypertensive therapy. RESULTS: The hazard ratios for cardiovascular disease (CVD) mortality for each 15 beats/min increase in RHR were 1.24 (1.11-1.40) in men and 1.32 (1.08-1.60) in women, adjusted for age, gender, total cholesterol, physical activity (categorical), SBP, body mass index, and high-density lipoprotein cholesterol. This relationship remained significant after exclusion of those with comorbidities and events occurring within first 2 years of observation. Relationship with coronary mortality was stronger and with total mortality was slightly weaker. Inclusion of nonfatal end points weakened the relationship. CONCLUSIONS: A strong, graded, independent relationship between RHR and incident CVD was demonstrated. This was consistent in healthy men and women. We have clarified that the relationship is independent of SBP and that the temporal sequence would be compatible with a causal relationship. New findings include independence from both a validated measure of physical activity and comorbidities and the demonstration of a stronger effect for fatal than nonfatal events, supporting increased arrhythmogenicity of one of the mechanisms.

Assessment of cardiovascular risk.

Atherosclerotic cardiovascular disease (CVD) is the most common cause of death worldwide. Usually atherosclerosis is caused by the combined effects of multiple risk factors. For this reason, most guidelines on the prevention of CVD stress the assessment of total CVD risk. The most intensive risk factor modification can then be directed towards the individuals who will derive the greatest benefit. To assist the clinician in calculating the effects of these multiple interacting risk factors, a number of risk estimation systems have been developed. This review address several issues regarding total CVD risk assessment: Why should total CVD risk be assessed? What risk estimation systems are available? How well do these systems estimate risk? What are the advantages and disadvantages of the current systems? What are the current limitations of risk estimation systems and how can they be resolved? What new developments have occurred in CVD risk estimation?

Critical analysis of the utility of initial pleural aspiration in the diagnosis and management of suspected malignant pleural effusion.

INTRODUCTION: Current guidelines recommend an initial pleural aspiration in the investigation and management of suspected malignant pleural effusions (MPEs) with the aim of establishing a diagnosis, identifying non-expansile lung (NEL) and, at times, providing a therapeutic procedure. A wealth of research has been published since the guidelines suggesting that results and outcomes from an aspiration may not always provide sufficient information to guide management. It is important to establish the validity of these findings in a 'real world' population. METHODS: A retrospective analysis was conducted of all patients who underwent pleural fluid (PF) sampling, in a single centre, over 3 years to determine the utility of the initial aspiration. RESULTS: A diagnosis of MPE was confirmed in 230/998 (23%) cases, a further 95/998 (9.5%) were presumed to represent MPE. Transudative biochemistry was found in 3% of cases of confirmed MPE. Positive PF cytology was only sufficient to guide management in 45/140 (32%) cases. Evidence of pleural thickening on CT was associated with both negative cytology (χ2 1df=26.27, p<0.001) and insufficient samples (χ2 1df=10.39, p=0.001). In NEL 44.4% of patients did not require further procedures after pleurodesis compared with 72.7% of those with expansile lung (χ2 1df=5.49, p=0.019). In patients who required a combined diagnostic and therapeutic aspiration 106/113 (93.8%) required further pleural procedures. CONCLUSIONS: An initial pleural aspiration does not achieve either definitive diagnosis or therapy in the majority of patients. A new pathway prioritising symptom management while reducing procedures should be considered.

How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators.

BACKGROUND: Systematic COronary Risk Evaluation (SCORE), the risk estimation system recommended by the European guidelines on cardiovascular disease prevention, estimates 10-year risk of cardiovascular disease mortality based on age, sex, country of origin, systolic blood pressure, smoking status and either total cholesterol (TC) or TC/high-density lipoprotein cholesterol (HDL-C) ratio. As, counterintuitively, these two systems perform very similarly, we have investigated whether incorporating HDL-C and TC as separate variables improves risk estimation. METHODS: The study consisted of 57,302 men and 47,659 women. Cox proportional hazards method was used to derive the function including HDL-C and an identical function without HDL-C for comparison. Risk charts were developed to illustrate the results. RESULTS: Inclusion of HDL-C resulted in a modest but statistically significant improvement in risk estimation, based on the area under receiver operating characteristic curve (AUROC); 0.814 versus 0.808, P value less than 0.0001, for the functions with and without HDL-C, respectively. Addition of HDL-C also resulted in a significant and important improvement in risk estimation as measured by net reclassification index, which is highly clinically relevant. Improvement in risk estimation was greatest in women from high-risk countries, in terms of both AUROC and net reclassification index. CONCLUSION: For the general population, the inclusion of HDL-C in risk estimation results in only a modest improvement in overall risk estimation based on AUROC. However, when using the more clinically that examines reclassification of individuals, clinically useful improvements occur. Inclusion of HDL may be particularly useful in women from high-risk countries and individuals with unusually high or low HDL-C levels. Addition of HDL-C is particularly applicable to electronic, interactive risk estimation systems such as HeartScore.

Re-evaluating the Rose approach: comparative benefits of the population and high-risk preventive strategies.

BACKGROUND: Options for the prevention of cardiovascular disease, the greatest global cause of death, include population preventive measures (the Rose approach), or specifically seeking out and managing high-risk cases. However, the likely benefit of a population approach has been recently questioned. OBJECTIVE: To compare the estimated effects of population strategies at varying levels of population-wide risk factor reduction and high-risk strategies at varying rates of screening uptake on cardiovascular disease mortality. METHODS: Data (of 109 954 participants) were pooled from six European general population cohort studies [the high-risk cohorts from the SCORE (Systematic COronary Risk Evaluation) dataset]. The effects of various population and high-risk strategies for the reduction of risk factors were estimated by calculating the change in 10-year risk of cardiovascular disease mortality (SCORE risk) before and after the particular intervention. Risk factors studied were: total cholesterol, blood pressure and smoking. RESULTS: At population level, if a 10-year reduction of blood cholesterol level of 10%, a BP reduction of 10% and a 10% reduction in the prevalence of smoking is considered possible, then 9125 lives per million of the population would be saved over 10 years. In contrast, an approach that treats all high-risk individuals with a polypill containing statin, three half-dose antihypertensives and aspirin, with a 20-80% uptake, would save 1861-7452 lives per million. However, the high-risk estimates are very optimistic, as their achievement would require complete compliance. CONCLUSION: High-risk and population strategies are complementary. These estimates of the benefits of each may be useful to health planners, when combined with their local knowledge. Recently, benefits of population strategies have been underestimated.

Dielectrophoresis-Assisted Integration of 1024 Carbon Nanotube Sensors into a CMOS Microsystem.

Carbon-nanotube (CNT)-based sensors offer the potential to detect single-molecule events and picomolar analyte concentrations. An important step toward applications of such nanosensors is their integration in large arrays. The availability of large arrays would enable multiplexed and parallel sensing, and the simultaneously obtained sensor signals would facilitate statistical analysis. A reliable method to fabricate an array of 1024 CNT-based sensors on a fully processed complementary-metal-oxide-semiconductor microsystem is presented. A high-yield process for the deposition of CNTs from a suspension by means of liquid-coupled floating-electrode dielectrophoresis (DEP), which yielded 80% of the sensor devices featuring between one and five CNTs, is developed. The mechanism of floating-electrode DEP on full arrays and individual devices to understand its self-limiting behavior is studied. The resistance distributions across the array of CNT devices with respect to different DEP parameters are characterized. The CNT devices are then operated as liquid-gated CNT field-effect-transistors (LG-CNTFET) in liquid environment. Current dependency to the gate voltage of up to two orders of magnitude is recorded. Finally, the sensors are validated by studying the pH dependency of the LG-CNTFET conductance and it is demonstrated that 73% of the CNT sensors of a given microsystem show a resistance decrease upon increasing the pH value.

Determinants of risk factor control in subjects with coronary heart disease: a report from the EUROASPIRE III investigators.

The EUROASPIRE audits of risk factor control have indicated that, even in those with established coronary heart disease, risk factor control remains poor. We therefore analysed the EUROASPRE III data set to establish the factors associated with success or failure in risk factor control in order to inform future risk factor management strategies. University education, attendance at a specialist cardiology clinic, and participation in a cardiac rehabilitation programme were associated with improved risk factor control. Risk factor control was poorer in women, those with diabetes, and those undergoing coronary artery bypass surgery as opposed to medical therapy or percutaneous coronary intervention. Increasing age, depression, and anxiety were not associated with poorer risk factor control.

Cardiovascular risk age: concepts and practicalities.

OBJECTIVES: A young person with many risk factors may have the same level of risk as an older person with no risk factors. Thus a high-risk 40-year-old may have a risk age of 60 years or more. The aim of the study was to derive a generic equation for risk age, construct risk age charts, and explore the hypothesis that risk age is similar regardless of the cardiovascular disease (CVD) end point used. METHODS: The equation was generated by equating the generic formula for 10-year CVD risk (with unknown risk factor levels) to the generic formula for 10-year CVD risk in a person with age = x and ideal risk factor levels (total cholesterol 4 mmol/l, systolic blood pressure 120 mm Hg, and non-smoker) and solving for x. To examine the consistency between risk ages for different end points, a risk age based on risk of CVD fatal events and based on risk of fatal and non-fatal CVD events was derived for each of the participants in the FINRISK population study. The correlation between these risk ages was examined. RESULTS: A generic equation for risk age was derived. The generic equation could not be used for SCORE (Systematic COronary Risk Evaluation), because the age is included in the baseline. Therefore a table of SCORE risk ages was developed by looking up the risk age corresponding to each combination of risk factors in the chart. Risk age remains similar regardless of the cardiovascular end point used, which bypasses the dilemma of whether to use a risk-estimation system based on CVD mortality or on the more attractive but less reliable end point of total CVD events. On the basis of the equation, risk age is not dependent on baseline survival and therefore recalibration is not required. CONCLUSIONS: Risk age is an intuitive and easily understood method for communicating about risk, particularly in younger patients, and may facilitate lifestyle change in younger patients. However, treatment decisions should be based on absolute risk, as recommended by guidelines on CVD prevention.

Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians.

Atherosclerotic cardiovascular diseases (CVDs) are the biggest causes of death worldwide. In most people, CVD is the product of a number of causal risk factors. Several seemingly modest risk factors may, in combination, result in a much higher risk than an impressively raised single factor. For this reason, risk estimation systems have been developed to assist clinicians to assess the effects of risk factor combinations in planning management strategies. In this article, the performances of the major risk estimation systems are reviewed. Most perform usably well in populations that are similar to the one used to derive the system, and in other populations if calibrated to allow for different CVD mortality rates and different risk factor distributions. The effect of adding "new" risk factors to age, sex, smoking, lipid status, and blood pressure is usually small, but may help to appropriately reclassify some of those patients who are close to a treatment threshold to a more correct "treat/do not treat" category. Risk estimation in the young and old needs more research. Quantification of the hoped-for benefits of the multiple risk estimation approach in terms of improved outcomes is still needed. But, it is likely that the widespread use of such an approach will help to address the issues of both undertreatment and overtreatment.

von Willebrand Factor in CHD and stroke: relationships and therapeutic implications.

Atherosclerotic cardiovascular disease (CVD), which includes coronary heart disease (CHD) and stroke, is now the most common cause of death in the middle aged and elderly in all parts of the world except subSaharan Africa. The direct cause of death is frequently an acute thrombotic arterial occlusion. Because atherosclerosis is a diffuse disease, patients with CHD also have a high risk of ischemic stroke. The hemostatic process is a needed defense mechanism to control hemorrhage after injury but at same time, if overactive, may have the potential to precipitate diseases such as myocardial infarction or stroke in the setting of atherosclerosis. In approximately 1% of all patients with ischemic stroke, and in up to 4% of young adults with stroke, the major precipitant of brain ischemia is a hematologic disorder or coagulopathy that predisposes to thrombosis. von Willebrand factor (vWF) plays an important role in platelet adhesion to subendothelial structures and in the intrinsic pathway of coagulation. It is regarded as an indirect measure of endothelial dysfunction. Deficiency of vWF in von Willebrand's disease is well established. However, much less is known regarding the pathophysiologic implications of an elevated level of vWF, particularly in relation to CVD and cerebrovascular disease. The importance of vWF in the pathogenesis of this disease is poorly defined and information is limited and inconsistent. Elevated levels of vWF have been variably linked with risk of CHD; causal criteria are not fully met. Relationships with stroke risk are even less well established. Measurement of vWF adds little to risk prediction after considering the major risk factors--age, sex, smoking, raised blood cholesterol, and hypertension. vWF may have a greater role in predicting outcome in subjects with acute coronary syndromes (ACS), stroke, and perhaps atrial fibrillation. Investigation of the use of vWF level to guide treatment of ACS or stroke is ongoing; however, there is no compelling evidence to date.