19 hours ago, from link: http://phys.org/news/2015-02-artificially-intelligent-robot-scientist-eve.html
Robot scientist 'Eve', based at the University of Manchester. Credit: University of Manchester
Eve, an artificially-intelligent 'robot scientist' could make drug discovery faster and much cheaper, say researchers writing in the Royal Society journal Interface. The team has demonstrated the success of the approach as Eve discovered that a compound shown to have anti-cancer properties might also be used in the fight against malaria.
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Robot scientists are a natural extension of the trend of increased involvement of automation in science. They can automatically develop and test hypotheses to explain observations, run experiments using laboratory robotics, interpret the results to amend their hypotheses, and then repeat the cycle, automating high-throughput hypothesis-led research. Robot scientists are also well suited to recording scientific knowledge: as the experiments are conceived and executed automatically by computer, it is possible to completely capture and digitally curate all aspects of the scientific process.
In 2009, Adam, a robot scientist developed by researchers at the Universities of Aberystwyth and Cambridge, became the first machine to independently discover new scientific knowledge. The same team has now developed Eve, based at the University of Manchester, whose purpose is to speed up the drug discovery process and make it more economical. In the study published today, they describe how the robot can help identify promising new drug candidates for malaria and neglected tropical diseases such as African sleeping sickness and Chagas' disease.
"Neglected tropical diseases are a scourge of humanity, infecting hundreds of millions of people, and killing millions of people every year," says Professor Steve Oliver from the Cambridge Systems Biology Centre and the Department of Biochemistry at the University of Cambridge. "We know what causes these diseases and that we can, in theory, attack the parasites that cause them using small molecule drugs. But the cost and speed of drug discovery and the economic return make them unattractive to the pharmaceutical industry.
Credit: Univeristy of Manchester
"Eve exploits its artificial intelligence to learn from early successes in her screens and select compounds that have a high probability of being active against the chosen drug target. A smart screening system, based on genetically engineered yeast, is used. This allows Eve to exclude compounds that are toxic to cells and select those that block the action of the parasite protein while leaving any equivalent human protein unscathed. This reduces the costs, uncertainty, and time involved in drug screening, and has the potential to improve the lives of millions of people worldwide."
Eve's robotic system is capable of screening over 10,000 compounds per day. However, while simple to automate, mass screening is still relatively slow and wasteful of resources as every compound in the library is tested. It is also unintelligent, as it makes no use of what is learnt during screening.
To improve this process, Eve selects at random a subset of the library to find compounds that pass the first assay; any 'hits' are re-tested multiple times to reduce the probability of false positives. Taking this set of confirmed hits, Eve uses statistics and machine learning to predict new structures that might score better against the assays. Although she currently does not have the ability to synthesise such compounds, future versions of the robot could potentially incorporate this feature.
Professor Ross King, from the Manchester Institute of Biotechnology at the University of Manchester, says: "Every industry now benefits from automation and science is no exception. Bringing in machine learning to make this process intelligent - rather than just a 'brute force' approach - could greatly speed up scientific progress and potentially reap huge rewards."
To test the viability of the approach, the researchers developed assays targeting key molecules from parasites responsible for diseases such as malaria, Chagas' disease and schistosomiasis and tested against these a library of approximately 1,500 clinically approved compounds. Through this, Eve showed that a compound that has previously been investigated as an anti-cancer drug inhibits a key molecule known as DHFR in the malaria parasite. Drugs that inhibit this molecule are currently routinely used to protect against malaria, and are given to over a million children; however, the emergence of strains of parasites resistant to existing drugs means that the search for new drugs is becoming increasingly more urgent.
"Despite extensive efforts, no one has been able to find a new antimalarial that targets DHFR and is able to pass clinical trials," adds Professor King. "Eve's discovery could be even more significant than just demonstrating a new approach to drug discovery."
More information: Williams, K. and Bilsland, E. et al. Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases. Interface; 4 Feb 2015. rsif.royalsocietypublishing.or… .1098/rsif.2014.1289
Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease.[2] The causes of cardiovascular disease are diverse but atherosclerosis and hypertension are the most common. In addition, with aging come a number of physiological and morphological changes that alter cardiovascular function and lead to increased risk of cardiovascular disease, even in healthy asymptomatic individuals.[3]
Cardiovascular diseases are the leading cause of deaths on the globally. According to a World Bank analysis, cardiovascular mortality has been declining in many high-income countries since 1970s.[4][5] At the same time, cardiovascular deaths and disease have increased at a fast rate in low- and middle-income countries.[6] Although cardiovascular disease usually affects older adults, the antecedents of cardiovascular disease, notably atherosclerosis, begin in early life, making primary prevention efforts necessary from childhood.[7] Consequently, there is increased emphasis on preventing atherosclerosis by modifying risk factors, for example by healthy eating, exercise, and avoidance of smoking tobacco and excessive alcohol intake.
There are several risk factors for heart diseases: age, gender, tobacco use, physical inactivity, excessive alcohol consumption, unhealthy diet, obesity, family history of cardiovascular disease, raised blood pressure (hypertension), raised blood sugar (diabetes mellitus), raised blood cholesterol (hyperlipidemia), psychosocial factors, poverty and low educational status, and air pollution.[2][9][10][11][12] While the individual contribution of each risk factor varies between different communities or ethnic groups the overall contribution of these risk factors is very consistent.[13] Some of these risk factors, such as age, gender or family history, are immutable; however, many important cardiovascular risk factors are modifiable by lifestyle change, social change, drug treatment and prevention of hypertension, hyperlipidemia, and diabetes.
Age
Calcified heart of an older woman with cardiomegaly.
Age is by far the most important risk factor in developing cardiovascular or heart diseases, with approximately a tripling of risk with each decade of life.[6] It is estimated that 82 percent of people who die of coronary heart disease are 65 and older.[14] At the same time, the risk of stroke doubles every decade after age 55.[15]
Multiple explanations have been proposed to explain why age increases the risk of cardiovascular/heart diseases. One of them is related to serum cholesterol level.[16] In most populations, the serum total cholesterol level increases as age increases. In men, this increase levels off around age 45 to 50 years. In women, the increase continues sharply until age 60 to 65 years.[16]
Aging is also associated with changes in the mechanical and structural properties of the vascular wall, which leads to the loss of arterial elasticity and reduced arterial compliance and may subsequently lead to coronary artery disease.[17]
Sex
Men are at greater risk of heart disease than pre-menopausal women.[6][18] Once past menopause, it has been argued that a woman's risk is similar to a man's[18] although more recent data from the WHO and UN disputes this.[6] If a female has diabetes, she is more likely to develop heart disease than a male with diabetes.[19]
Coronary heart diseases are 2 to 5 times more common among middle-aged men than women.[16] In a study done by the World Health Organization, sex contributes to approximately 40% of the variation in sex ratios of coronary heart disease mortality.[20] Another study reports similar results finding that gender differences explains nearly half the risk associated with cardiovascular diseases[16] One of the proposed explanations for gender differences in cardiovascular diseases is hormonal difference.[16] Among women, estrogen is the predominant sex hormone. Estrogen may have protective effects through glucose metabolism and hemostatic system, and may have direct effect in improving endothelial cell function.[16] The production of estrogen decreases after menopause, and this may change the female lipid metabolism toward a more atherogenic form by decreasing the HDL cholesterol level while increasing LDL and total cholesterol levels.[16]
Among men and women, there are notable differences in body weight, height, body fat distribution, heart rate, stroke volume, and arterial compliance.[17] In the very elderly people, age-related large artery pulsatility and stiffness is more pronounced among women than men.[17] This may be caused by the women's smaller body size and arterial dimensions which are independent of menopause.[17]
Tobacco
Cigarettes are the major form of smoked tobacco.[21] Risks to health from tobacco use result not only from direct consumption of tobacco, but also from exposure to second-hand smoke.[21]
Approximately 10% of cardiovascular disease is attributed to smoking,[21] however people who quit smoking by age 30 have almost as low a risk of death as never smokers.[22]
Physical inactivity
Insufficient physical activity (defined as less than 5 x 30 minutes of moderate activity per week, or less than 3 x 20 minutes of vigorous activity per week) is currently the fourth leading risk factor for mortality worldwide.[21] In 2008, 31.3% of adults aged 15 or older (28.2% men and 34.4% women) were insufficiently physically active.[21] The risk of ischemic heart disease and diabetes mellitus is reduced by almost a third in adults who participate in 150 minutes of moderate physical activity each week (or equivalent).[23] In addition, physical activity assists weight loss and improves blood glucose control, blood pressure, lipid profile and insulin sensitivity. These effects may, at least in part, explain its cardiovascular benefits.[21]
Excessive alcohol consumption
The relationship between alcohol consumption and cardiovascular disease is complex, and may depend on the amount of alcohol consumed. There is a direct relationship between high levels of alcohol consumption and risk of cardiovascular disease.[21] Drinking at low levels without episodes of heavy drinking may be associated with a reduced risk of cardiovascular disease.[24] Overall alcohol consumption at the population level is associated with multiple health risks that exceed any potential benefits.[21][25]
Unhealthy diet
High dietary intakes of saturated fat, trans-fats and salt, and low intake of fruits, vegetables and fish are linked to cardiovascular risk, although whether all these associations are causal is disputed. The World Health Organization attributes approximately 1.7 million deaths worldwide to low fruit and vegetable consumption.[21] The amount of dietary salt consumed is also an important determinant of blood pressure levels and overall cardiovascular risk.[21] Frequent consumption of high-energy foods, such as processed foods that are high in fats and sugars, promotes obesity and may increase cardiovascular risk.[21] High trans-fat intake has adverse effects on blood lipids and circulating inflammatory markers,[26] and elimination of trans-fat from diets has been widely advocated.[27]
There is evidence that higher consumption of sugar is associated with higher blood pressure and unfavorable blood lipids,[28] and sugar intake also increases the risk of diabetes mellitus.[29] High consumption of processed meats is associated with an increased risk of cardiovascular disease, possibly in part due to increased dietary salt intake.[30]
Socioeconomic disadvantage
Cardiovascular disease affects low- and middle-income countries even more than high-income countries.[31] There is relatively little information regarding social patterns of cardiovascular disease within low- and middle-income countries,[31] but within high-income countries low income and low educational status are consistently associated with greater risk of cardiovascular disease.[32] Policies that have resulted in increased socio-economic inequalities have been associated with greater subsequent socio-economic differences in cardiovascular disease [31] implying a cause and effect relationship. Psychosocial factors, environmental exposures, health behaviours, and health-care access and quality contribute to socio-economic differentials in cardiovascular disease. [33] The Commission on Social Determinants of Health recommended that more equal distributions of power, wealth, education, housing, environmental factors, nutrition, and health care were needed to address inequalities in cardiovascular disease and non-communicable diseases. [34]
Air pollution
Particulate matter has been studied for its short- and long-term exposure effects on cardiovascular disease. Currently, PM2.5 is the major focus, in which gradients are used to determine CVD risk. For every 10 μg/m3 of PM2.5 long-term exposure, there was an estimated 8–18% CVD mortality risk.[35]
Women had a higher relative risk (RR) (1.42) for PM2.5 induced coronary artery disease than men (0.90) did.[35] Overall, long-term PM exposure increased rate of atherosclerosis and inflammation. In regards to short-term exposure (2 hours), every 25 μg/m3 of PM2.5 resulted in a 48% increase of CVD mortality risk.[36] In addition, after only 5 days of exposure, a rise in systolic (2.8 mmHg) and diastolic (2.7 mmHg) blood pressure occurred for every 10.5 μg/m3 of PM2.5.[36] Other research has implicated PM2.5 in irregular heart rhythm, reduced heart rate variability (decreased vagal tone), and most notably heart failure.[36][37] PM2.5 is also linked to carotid artery thickening and increased risk of acute myocardial infarction.[36][37]
Pathophysiology
Density-Dependent Colour Scanning Electron Micrograph SEM (DDC-SEM) of cardiovascular calcification, showing in orange calcium phosphate spherical particles (denser material) and, in green, the extracellular matrix (less dense material).[38]
Population-based studies show that atherosclerosis, the major precursor of cardiovascular disease, begins in childhood. The Pathobiological Determinants of Atherosclerosis in Youth Study demonstrated that intimal lesions appear in all the aortas and more than half of the right coronary arteries of youths aged 7–9 years.[39]
This is extremely important considering that 1 in 3 people die from complications attributable to atherosclerosis. In order to stem the tide, education and awareness that cardiovascular disease poses the greatest threat, and measures to prevent or reverse this disease must be taken.
Obesity and diabetes mellitus are often linked to cardiovascular disease,[40] as are a history of chronic kidney disease and hypercholesterolaemia.[41] In fact, cardiovascular disease is the most life-threatening of the diabetic complications and diabetics are two- to four-fold more likely to die of cardiovascular-related causes than nondiabetics.[42][43][44]
Screening
Screening ECGs (either at rest or with exercise) are not recommended in those without symptoms who are at low risk.[45] This includes those who are young without risk factors.[46] In those at higher risk the evidence for screening with ECGs is inconclusive.[45]
Some biomarkers may add to conventional cardiovascular risk factors in predicting the risk of future cardiovascular disease; however, the clinical value of some biomarkers is still questionable.[47][48] Currently, biomarkers that may reflect a higher risk of cardiovascular disease include the following:
Currently practiced measures to prevent cardiovascular disease include:
A low-fat, high-fiber diet including whole grains and fruit and vegetables.[52][53] Five portions a day reduces risk by about 25%.[54]
Tobacco cessation and avoidance of second-hand smoke[52]
Limit alcohol consumption to the recommended daily limits[52] consumption of 1–2 standard alcoholic drinks per day may reduce risk by 30%[55][56] However excessive alcohol intake increases the risk of cardiovascular disease.[57]
Increase daily activity to 30 minutes of vigorous exercise per day at least five times per week (multiply by three if horizontal);[52]
Reduce sugar consumptions
Decrease psychosocial stress.[59] This measure may be complicated by imprecise definitions of what constitute psychosocial interventions.[60] Mental stress–induced myocardial ischemia is associated with an increased risk of heart problems in those with previous heart disease.[61] Severe emotional and physical stress leads to a form of heart dysfunction known as Takotsubo syndrome in some people.[62] Stress however plays a relatively minor role in hypertension.[63] Specific relaxation therapies are of unclear benefit.[64][65]
For adults without a known diagnosis of hypertension, diabetes, hyperlipidemia, or cardiovascular disease, routine counseling to advise them to improve their diet and increase their physical activity has not been found to significantly alter behavior, and thus is not recommended.[66] It is unclear whether or not dental care in those with periodontitis affects the risk of cardiovascular disease.[67]
Exercise in those who are at high risk of heart disease has not been well studied as of 2014.[68]
Diet
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death.[54] Evidence suggests that the Mediterranean diet may improve cardiovascular outcomes.[69] There is also evidence that a Mediterranean diet may be more effective than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).[70] The DASH diet (high in nuts, fish, fruits and vegetables, and low in sweets, red meat and fat) has been shown to reduce blood pressure,[71] lower total and low density lipoprotein cholesterol[72] and improve metabolic syndrome;[73] but the long term benefits outside the context of a clinical trial have been questioned.[74] A high fiber diet appears to lower the risk.[75]
Total fat intake does not appear to be an important risk factor.[76][77] A diet high in trans fatty acids; however, does appear to increase rates of cardiovascular disease.[77][78] Worldwide, dietary guidelines recommend a reduction in saturated fat.[79] However, there are some questions around the effect of saturated fat on cardiovascular disease in the medical literature.[80][81] A 2014 review did not find evidence of harm from saturated fats.[78] A 2012 Cochrane review found suggestive evidence of a small benefit from replacing dietary saturated fat by unsaturated fat.[82] A 2013 meta analysis concludes that substitution with omega 6 linoleic acid (a type of unsaturated fat) may increase cardiovascular risk.[79] Replacement of saturated fats with carbohydrates does not change or may increase risk.[83][84] Benefits from replacement with polyunsaturated fat appears greatest[77][85] however supplementation with omega-3 fatty acids (a type of polysaturated fat) does not appear to have an effect.[86]
The effect of a low-salt diet is unclear. A Cochrane review concluded that any benefit in either hypertensive or normal-tensive people is small if present.[87] In addition, the review suggested that a low-salt diet may be harmful in those with congestive heart failure.[87] However, the review was criticized in particular for not excluding a trial in heart failure where people had low-salt and -water levels due to diuretics.[88] When this study is left out, the rest of the trials show a trend to benefit.[88][89] Another review of dietary salt concluded that there is strong evidence that high dietary salt intake increases blood pressure and worsens hypertension, and that it increases the number of cardiovascular disease events; the latter happen both through the increased blood pressure and, quite likely, through other mechanisms.[90][91] Moderate evidence was found that high salt intake increases cardiovascular mortality; and some evidence was found for an increase in overall mortality, strokes, and left ventricular hypertrophy.[90]
Supplements
While a healthy diet is beneficial, in general the effect of antioxidant supplementation (vitamin E, vitamin C, etc.) or vitamins has not been shown to protection against cardiovascular disease and in some cases may possibly result in harm.[92][93] Mineral supplements have also not been found to be useful.[94]Niacin, a type of vitamin B3, may be an exception with a modest decrease in the risk of cardiovascular events in those at high risk.[95][96]Magnesium supplementation lowers high blood pressure in a dose dependent manner.[97] Magnesium therapy is recommended for patients with ventricular arrhythmia associated with torsades de pointes who present with long QT syndrome as well as for the treatment of patients with digoxin intoxication-induced arrhythmias.[98] Evidence to support omega-3 fatty acid supplementation is lacking.[99]
Medication
Aspirin has been found to be of only modest benefit in those at low risk of heart disease as the risk of serious bleeding is almost equal to the benefit with respect to cardiovascular problems.[100] In those at really low risk it is not recommended.[101]
Statins are effective in preventing further cardiovascular disease in people with a history of cardiovascular disease.[102] As the event rate is higher in men than in women, the decrease in events is more easily seen in men than women.[102] In those without cardiovascular disease but risk factors statins appear to also be beneficial with a decrease in mortality and further heart disease.[103] The time course over which statins provide preventation against death appears to be long, of the order of one year, which is much longer than the duration of their effect on lipids.[104] The medications niacin, fibrates and CETP Inhibitors, while they may increase HDL cholesterol do not affect the risk of cardiovascular disease in those who are already on statins.[105]
Management
Cardiovascular disease is treatable with initial treatment primarily focused on diet and lifestyle interventions.[106][107][108]
Epidemiology
Disability-adjusted life year for cardiovascular diseases per 100,000 inhabitants in 2004.[109]
no data
<900 p="">
900-1650
1650-2300
2300-3000
3000-3700
3700-4400
4400-5100
5100-5800
5800-6500
6500-7200
7200–7900
>7900
Cardiovascular diseases are the leading cause of death. In 2008, 30% of all global death is attributed to cardiovascular diseases. Death caused by cardiovascular diseases are also higher in low- and middle-income countries as over 80% of all global death caused by cardiovascular diseases occurred in those countries. It is also estimated that by 2030, over 23 million people will die from cardiovascular diseases each year.
Research
The first studies on cardiovascular health were performed in year 1949 by Jerry Morris using occupational health data and were published in year 1958.[110] The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis.
A fairly recent emphasis is on the link between low-grade inflammation that hallmarks atherosclerosis and its possible interventions. C-reactive protein (CRP) is a common inflammatory marker that has been found to be present in increased levels in patients who are at risk for cardiovascular disease.[111] Also osteoprotegerin, which is involved with regulation of a key inflammatory transcription factor called NF-κB, has been found to be a risk factor of cardiovascular disease and mortality.[112][113]
Some areas currently being researched include the possible links between infection with Chlamydophila pneumoniae (a major cause of pneumonia) and coronary artery disease. The Chlamydia link has become less plausible with the absence of improvement after antibiotic use.[114]
Several research also investigated the benefits of melatonin on cardiovascular diseases prevention and cure. Melatonin is a pineal gland secretion and it is shown to be able to lower total cholesterol, very-low-density and low-density lipoprotein cholesterol levels in the blood plasma of rats. Reduction of blood pressure is also observed when pharmacological doses are applied. Thus, it is deemed to be a plausible treatment for hypertension. However, further research needs to be conducted to investigate the side-effects, optimal dosage, etc. before it can be licensed for use.[115]
Maternal factors and
complications of pregnancy,
labour and delivery
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