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By Z. Hernando. University of Idaho.

This command sequence can then be repeated to obtain the following tables and statis- tics for questions 2 and 3 of the questionnaire purchase tadacip 20mg with mastercard. From the Crosstabulation table for question 1 buy tadacip 20 mg overnight delivery, the per cent in agreement is estimated from the per cent who are concordant, which is shown on the diagonal of the table in the No at Time 1-No at Time 2 and Yes at Time 1-Yes at Time 2 cells. The Symmetric Measures table Tests of reliability and agreement 319 shows that the P value of 0. Since the level of significance is two-tailed, the P value does not indicate whether the agreement is worse or better than chance. However, agreement worse than that expected by chance rarely occurs in clinical contexts. It should be noted that the P value is not a good indication of reliability because its interpretation is that the kappa value is significantly different from zero. Measurements taken from the same people on two occasions are closely related by nature and thus 320 Chapter 10 the P value is expected to indicate some degree of agreement. The standard error is also reported and can be used to calculate a confidence interval around kappa. In the Crosstabulation table for question 2, the per cent in agreement is 68% + 10%, which is 78% or 0. Crosstabs Question 2 − Time 1 * Question 2 − Time 2 crosstabulation Question 2 − time 2 No Yes Total Question 2 − time 1 No Count 34 5 39 Percentage of total 68. In the Crosstabulation table for question 3, although the per cent in agreement is 34% + 44%, which is also 78% or 0. With a higher per cent of ‘Yes’ replies (56% for question 3 compared with 22% for question 2), kappa increases from the fair to moderate range. Crosstabs Question 3 − Time 1 * Question 3 − Time 2 crosstabulation Question 3 − time 2 No Yes Total Question 3 − time 1 No Count 17 5 22 Percentage of total 34. Tests of reliability and agreement 321 A feature of kappa is that the value increases as the proportion of ‘No’ and ‘Yes’ responses become more equal and when the proportion in agreement remains the same. This feature is a major barrier to comparing kappa values across measurements or between different studies. For this reason, the value of kappa, the percentage of positive responses and the per cent in agreement must all be reported to help assess reliability and agreement. It is difficult to say which question is the most reliable and has the least non-systematic bias because all three questions have a different percentage of positive responses and therefore the kappa values cannot be compared. However, both questions 2 and 3 have a higher per cent in agreement than question 1. The differences in per- centages of positive responses suggest that the three questions are measuring different entities. A measure is reliable if it produces the same value under all possible situations, that is, with different raters, in different settings and at different times. A measurement that has poor reliability will not be accurate at measuring the construct that it has been designed to measure and will also be unstable over repeated adminis- trations, that is have poor test–retest reliability. Variations in continuous measurements can result from inconsistent measurement practices, from equipment variations or from ways in which results are read or interpreted. These sources can be measured as within-rater (intra-rater) variation, between-rater (inter-rater) variation, or within-participant variation (see Table 10. Variations that result from the ways in which researchers administer, read, or interpret tests are within-rater or between-rater variations. Variations that arise from patient 322 Chapter 10 compliance factors or from biological changes are within-participant variations. To quantify these measurement errors, the same measurement is taken from the same participants on two occasions, or from the same participants by two or more raters, and the results are compared. The remaining 5% of the variance is due to measurement error or the variance within the participants or between the raters. That is, there are different raters and not the same raters are used for all participants. This is the model most frequently encountered in clinical research when the same raters carry out measurements on all of the participants. This is uncommon because the raters usually represent an unlimited number of people who could make the observations. The value for ‘single measures’ statistic is an index of reliability for typical single raters, which is the most common situation in clinical research.

Founding members of the alliance have already begun to collaborate on solutions that target common technology problems faced by life science companies discount tadacip 20mg amex. The first of these solutions is the Collaborative Molecular Environment generic 20 mg tadacip amex, which will provide a means for data capture, visualization, annotation and archiving using Microsoft® Office, Windows® Presentation Foundation and SharePoint® Technologies. In addition to making data easier to manage, early efforts of the alliance are focused on making data easier to share. Most efforts to unite the life science and infor- mation technology industries are focused on developing technology to enable the early-stage drug discovery process. By addressing the technology issues that com- panies face throughout the development cycle and by working with some of world’s top technology providers, the alliance will help the industry move closer to making personalized medicine a reality. Role of the Clinical Laboratories The role of the clinical laboratories in pharmacogenomics is established now, as there are several such facilities that provide technologies to improve the efficacy and safety in drugs by using genetic testing to determine patient therapy. Currently, clinical laboratories assist pharmaceutical sponsors in preclinical pharmacogenetic testing. In the future clinical laboratories will participate in genetic test develop- ment and validation, high-throughput genotyping of patients in clinical trials, and personalized medicine. However, when molecular diagnostic technology advances to point-of-care stage, a patient’s genotype may be determined on the spot and not sent to a labora- tory. Similarly, with merging of diagnostics and therapeutics in integrated health- care, diagnostic kits may be sold along with the therapeutics and laboratory procedures would be done at the comprehensive healthcare clinics. Clinical labora- tories, however, will continue to serve pharmaceutical industry during the drug development stage. Moreover, the quality control of such testing or regulatory oversight may not be possible unless an approved laboratory conducts these tests. To keep up with the challenges of the future, clinical laboratories will have to get involved in research in pharmacogenomic technologies and participate in the development of tests. Once the molecule is Universal Free E-Book Store Role of Life Sciences Industries 599 labeled, it is injected into the patient. The positrons that are emitted from the isotopes then interact locally with negatively charged electrons and emit what is called anni- hilating radiation. It is the timing and position of the detection that indicates the position of the molecule in time and space. Images can then be constructed tomographically, and regional time activities can be derived. The kinetic data produced provide information about the biological activity of the molecule. Molecular imaging provides in vivo information in contrast to the in vitro diagnostics. Moreover, it provides a direct method for the study of the effect of a drug in the human body. Personalized medicine will involve the integration of in vitro genotyping and in vivo phenotyping techniques. These modalities along with ultrasound and optical imaging (bioluminescence, fluorescence, near- infrared imaging, multispectral imaging) have become used increasingly in pre- clinical studies in animal models to document the effects of genetic alterations on cancer progression or metastases, the detection of minimal residual disease, and response to various therapeutics including radiation, chemotherapy, or biologic agents. The field of molecular imaging offers potential to deliver a variety of probes that can image noninvasively drug targets, drug distribution, cancer gene expres- sion, cell surface receptor or oncoprotein levels, and biomarker predictors of prog- nosis, therapeutic response, or failure. Some applications are best suited to accelerate preclinical anticancer drug development, whereas other technologies may be directly transferable to the clinic. Efforts are underway to apply noninvasive in vivo imaging to specific preclinical or clinical problems to accelerate progress in the field. By enabling better patient selection and treatment monitoring strategies, molecular imaging will likely reduce the future cost of drug development. As anticancer strategies become more directed towards a defined molecular tar- get, we need information that is relevant to humans about whether the molecular target is expressed, the selectivity and binding of the compound for that target, and the effects of such an interaction. The following is an example of the use of molecu- lar imaging in drug discovery for cancer. The use of noninvasive bioluminescence imaging has been demonstrated in a high-throughput cell-based screen of small molecules that activate p53 responses and cell death in human tumor cells carrying a mutant p53 Universal Free E-Book Store 600 20 Development of Personalized Medicine (Wang et al. Some compounds do not induce significant p73 expression but induce a high p53-responsive transcriptional activity in the absence of p53. The results establish the feasibility of a cell-based drug screening strategy targeting the p53 transcription factor family of importance in human cancer and provide lead compounds for further development in cancer therapy. These findings emphasize the growing role of imaging technology in aiding researchers in the development of personalized cancer treatments.

Organs for perception cheap tadacip 20mg online, limbs and other parts of the body are assumed to be connected to each other and to a centre via cer- tain ‘passages’ (poroi cheap tadacip 20 mg without prescription, phlebes, neura). The assumption of the existence of this network of passages and the ideas about their course and ramifications are highly speculative and hardly based on what we would 21 On Youth and Old Age (De iuventute et senectute, De iuv. Yet the fact that this obser- vation was known both to the author of the Hippocratic work On Fleshes and to Aristotle, who nevertheless do not attribute any significant role in cognition to the brain, proves that it might equally give rise to other interpretations. The authors mentioned do in fact employ rather sophisticated termi- nology for what we would call psychological, mental or spiritual faculties, but they assume a close connection between these faculties and anatomical and physiological factors. When speaking about exercising these faculties, they virtually always do so in terms of certain substances (such as blood, air or water) or qualities (hot, cold, dry, wet) and of processes such as flowing and distributing or, in case the psychic faculties have been disturbed, of stagnation, constipation, blockage, and so on. Another recurring element is the emphasis on balance (isonomia, summetria, eukrasia) and on the risk of an excess or shortage of a certain substance or quality. An exception to this rule is Aristotle’s idea that the highest cognitive faculty, thought, is not bound to a physical substrate. It is a kind of epiphe- nomenon that, although it is unable to function without sense perception (and therefore without physiological processes), cannot be located in a par- ticular place of the body. The author of this presumably post-Aristotelian writing claims that gnome¯ ¯ (‘mind’, ‘insight’) has its seat in the left ventricle of the heart, from where it issues its decrees about ‘the other (part of the) soul’ (alle¯ psuche¯), which is situated in the rest of the body. To prove his stance, the author argues that if autopsy were carried out on a body of a living being that had just been killed, the aorta would still contain blood, but the left 28 See Lloyd (1979) 146–9; for views on the vascular system see the studies mentioned in Harris (1973) and Duminil (1983). As stated above, the heart is given a leading role in co-ordinating perception, movement and nutrition (see Part. For the problems raised by Aristotle’s view see Barnes (1971–2) 110–12, reprinted in Barnes, Schofield and Sorabji, vol. Heart, brain, blood, pneuma 131 ventricle would not;31 this maintains contact with the blood by means of a process of ‘evaporation’ and ‘radiation’. As we have seen before, the medical authors of the period we are discussing do not consider the question of the seat of the mind an isolated issue, but a matter that becomes relevant when treating diseases which, although they have a somatic cause like other diseases, also manifest themselves in psychic disor- ders. Of the four classic psychosomatic diseases, mania (a chronic disorder), phrenitis, melancholia and epilepsy, epilepsy was by far the most dreaded. It was also known as ‘the big disease’ or ‘the sacred disease’; possession by the gods seemed the obvious explanation, but at the same time the physical aspects of the disease were so prominent that there could be no doubt as to its pathological status (as opposed to mania and melancholia, which were considered to manifest themselves in positive forms as well). After a long philippic against those adhering to this view he expounds his own theory. Epilepsy is the result of an accumu- lation of phlegm (phlegma) in the passages that divide themselves from the brain throughout the body and enable the distribution of the vital pneuma (this air is indispensable for the functioning of the various organs). This accumulation is a result of insufficient prenatal or postnatal ‘purifi- cation’ (katharsis) of phlegm in the brain – according to the author this is a hereditary phenomenon. This obstruction can occur in different places in the body and, accordingly, manifest itself in different symptoms. Near the heart, it will result in palpitations and asthmatic complaints; in the abdomen, in diarrhoea; in the ‘veins’, in foaming at the mouth, grinding of teeth, clenched hands, rolling eyes, disorders in consciousness, and a lack of bowel control. This way the author explains the various symptoms that can present themselves during epileptic fits and which he describes in considerable detail in chapter 7 of the treatise. The brain is the ‘cause’ (aitios)of the disease, and its condition can be influenced by a number of external causal factors (prophaseis) such as age, climate, season, the right or left side of the body, and the like. A haematocentric approach to epilepsy can be found in the Hippocratic writing On Breaths. The author of this highly rhetorical treatise (probably written at the end of the fifth century bce) assigns a pivotal role to air (pneuma, phusa) in the life of organisms. He takes the view that the main cause of diseases consists in a shortage or excess of air in the body or in the contaminated state of this air. This may either have external causes or be due to bad digestion of food, which also contains air, in the body (for instance because there is too much of it in the body) which causes all kinds of harmful gases to form. Such a disturbing effect of air due to a surplus of it is also what causes the ‘so-called sacred disease’. It is again striking how the author incorporates the empirically perceptible phenomena of the disease in his own explanation: In my view, the same cause is also responsible for the disease called sacred. I believe that none of the parts of the body that contribute to consciousness in any- one is more important than blood. So long as this remains in a stable condition, consciousness, too, remains stable; but when the blood undergoes change, con- sciousness also changes.

In short order tadacip 20mg otc, this doxographic distortion attributes to doctors and philosophers answers to questions which some of them would not even be able or willing to answer as a matter of principle buy tadacip 20mg lowest price. Finally, Caelius Aurelianus upholds a long tradition of contempt for the so-called phusiologia. This tradition dates back to the author of the Hippocratic writing On Ancient Medicine (c. He was opposed to some of his colleagues’ tendency to build their medical practice on general and theoretical principles or ‘postulates’ (hupotheseis) derived from 9 Aristotle lists a range of terms for cognitive faculties (nous, phronesis¯ , episteme¯ ¯, sophia, gnome¯ ¯, sunesis, doxa, hupolepsis¯ ) in book 6 of the Nicomachean Ethics; however, it remains uncertain to what extent the subtle differences in meaning that Aristotle ascribes to these terms are representative for Greek language in general. Heart, brain, blood, pneuma 123 natural philosophy, such as the so-called four primary qualities hot, cold, dry and wet. By contrast, he adopted a predominantly empirical approach to medicine, which in his view was tantamount to dietetics, the theory of healthy living. His approach was based on insights into the wholesome effects of food, insights that had been passed down from generation to generation and refined by experimentation. He even went so far as to claim that in reality physics does not form the basis for medicine, but medicine for physics. The question of to what extent a doctor should be concerned with, or even build on, principles derived from physics (or metaphysics) remained a matter of dispute throughout antiquity. What made the problem even more urgent was that in many areas of controversy, such as that on the location of the mind, it remained unclear to what extent these could be resolved on empirical grounds. The doctor’s desire to build views concerning the correct diagnosis and treatment of psychosomatic disorders such as mania, epilepsy, lethargy, melancholia and phrenitis on a presupposition about the location of the psychic faculties affected, which could not be proved empirically, differed according to his willingness to accept such principles, which were sometimes complimentarily, sometimes condescendingly labelled ‘philo- sophical’. They corresponded to an ideal proclaimed first by Aristotle and later by Galen, namely that of the ‘civilised’ or ‘distinguished’ physician, who is both a competent doctor and a philosopher skilled in physics, logic, and rhetoric. Yet in this dispute, too, the variety of views on the matter was much wider than his general characterisation suggests. It is therefore highly likely that Caelius Aurelianus’ presentation intends to exaggerate the differences in opinion between the doctors mentioned, in order to make his own view stand out more clearly and simply against the background of confusion generated by others. These introductory observations may suffice to provide an outline of the debate on the seat of the mind, which was the subject of fierce dispute 10 The first time the word philosophia is attested in Greek literature is in ch. The word is used in a clearly negative sense, to describe the practice of scrounging from physics, which is rejected by the author. Galen wrote a separate treatise entitled and devoted to the proposition that The Best Physician is also a Philosopher (i. In so far as antiquity is concerned, there were at least three causes for this: the reasons for asking the question (and the desire to answer it) differed depending on whether one’s purposes were medical, philosophical or purely rhetorical; the status of the arguments for or against a certain answer (such as the evidential value of medical experiments) was subject to fluctuation; and the question itself posed numerous other problems related to the (to this day) disputed area of philosophical psychology or ‘philosophy of the mind’, such as the question of the relationship between body and soul, or of the difference between the various ‘psychic’ faculties, and so on. When following the debate from its in- ception until late antiquity, one gets the impression that the differences manifest themselves precisely in these three areas. Whereas the doctors of the Hippocratic Corpus were mainly interested in the question of the location of the mind in so far as they felt a need for a treatment of psycho- logical disorders based on a theory of nature, later the situation changed and medical-physiological data were no more than one of the possible (but by no means decisive) factors to build arguments for one of the positions taken on. In the section below I will pay particular attention to the early phase of the debate (fifth and fourth centuries bce), concentrating on the main authors of the Hippocratic Corpus, Aristotle and Diocles, with brief references to Plato. Secondary literature on this issue usually distinguishes between the encephalocentric, cardiocentric and haematocen- tric view on the seat of the mind. A selection from the extensive range of literature on this subject: Bidez and Leboucq (1944); Byl (1968); Di Benedetto (1986) 35–69; Duminil (1983); Gundert (2000); Hankinson (1991b); Harris (1973); Manuli (1977); Pigeaud (1981b) 72; Pigeaud (1980); Pigeaud (1987); Revesz (1917); Rusche (¨ 1930); B. Heart, brain, blood, pneuma 125 taken by the fifth-century medical writer Alcmaeon of Croton (South Italy), who was thought to be the first to discover the existence of the optic nerve, by the author of the Hippocratic work On the Sacred Disease, and by Plato (in the Timaeus). The cardiocentric view was represented in the Hippo- cratic writings On Diseases 2 (fifth century bce), On the Heart (end of the fourth/start of the third century bce) and by Aristotle, Diocles of Carystus and Praxagoras of Cos (fourth century bce). The haematocentric view was taken by Empedocles and the authors of the Hippocratic writings On Dis- eases 1 and On Breaths (all fifth century bce). Although this division may be largely appropriate in terms of the period concerned, it is already too much a product of the schematisation mentioned above, which became characteristic of the debate in later doxography. Strictly speaking, only the authors of On the Sacred Disease and On the Heart express an opinion on the location of what they consider the highest psychic faculty, the former choos- ing the brain, the latter the heart.