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This decrease is similar to that reported from autopsy data in Japan (mean 1 cheap 50mg nizagara visa erectile dysfunction at 17,422 to 1 50 mg nizagara fast delivery list all erectile dysfunction drugs,336 g) (Yamaura et al. Whether glucose oxidation changes out of proportion to brain mass remains a controversial issue (Gottstein and Held, 1979; Leenders et al. In any case, the decrease in brain glucose oxidation rate is not likely to be substantially less. There is no evidence to indicate that a certain amount of carbohydrate should be provided as starch or sugars. However, most individuals do not choose to eat a diet in which sugars exceed approximately 30 percent of energy (Nuttall and Gannon, 1981). This increased fuel requirement is due to the establish- ment of the placental–fetal unit and an increased energy supply for growth and development of the fetus. It is also necessary for the maternal adapta- tion to the pregnant state and for moving about the increased mass of the pregnant woman. This increased need for metabolic fuel often includes an increased maternal storage of fat early in pregnancy, as well as suffi- cient energy to sustain the growth of the fetus during the last trimester of pregnancy (Knopp et al. In spite of the recognized need for increased energy-yielding substrates imposed by pregnancy, the magnitude of need, as well as how much of the increased requirement needs to be met from exogenous sources, remains incompletely understood and is highly variable (Tables 5-23 through 5-27). There is general agreement that the additional food energy requirement is relatively small. Several doubly labeled water studies indicate a progres- sive increase in total energy expenditure over the 36 weeks of pregnancy (Forsum et al. The mean difference in energy expenditure between week 0 and 36 in the studies was approximately 460 kcal/d and is proportional to body weight. The fetus does not utilize significant amounts of free fatty acids (Rudolf and Sherwin, 1983). As part of the adaptation to pregnancy, there is a decrease in maternal blood glucose concentration, a development of insulin resistance, and a tendency to develop ketosis (Burt and Davidson, 1974; Cousins et al. A higher mean respiratory quotient for both the basal metabolic rate and total 24-hour energy expenditure has also been reported in pregnant women when compared to the postpartum period. The increased glucose utilization rate persists after fasting, indicating an increased endogenous production rate as well (Assel et al. Thus, irrespective of whether there is an increase in total energy expenditure, these data indicate an increase in glucose utilization. Earlier, it was reported that the glucose turnover in the overnight fasted state based on maternal weight gain remains unchanged from that in the nonpregnant state (Cowett et al. The fetus reportedly uses approximately 8 ml O2/kg/min or 56 kcal/ kg/d (Sparks et al. The transfer of glucose from the mother to the fetus has been estimated to be 17 to 26 g/d in late gestation (Hay, 1994). If this is the case, then glucose can only account for approximately 51 percent of the total oxidizable substrate transferred to the fetus at this stage of gestation. The mean newborn infant brain weight is reported to be approximately 380 g (Dekaban and Sadowsky, 1978). Assuming the glucose consumption rate is the same for infants and adults (approximately 33 µmol/100 g of brain/min or 8. This is greater than the total amount of glucose transferred daily from the mother to the fetus. Data obtained in newborns indicate that glucose oxidation can only account for approximately 70 percent of the brain’s estimated fuel require- ment (Denne and Kalhan, 1986). In addition, an increase in circulating ketoacids is common in pregnant women (Homko et al. Taken together, these data suggest that ketoacids may be utilized by the fetal brain in utero. If nonglucose sources (largely ketoacids) supply 30 percent of the fuel requirement of the fetal brain, then the brain glucose utilization rate would be 23 g/d (32. These data also indicate that the fetal brain utilizes essentially all of the glucose derived from the mother. There is no evidence to indicate that a certain portion of the carbohydrate must be consumed as starch or sugars. The lactose content of human milk is approximately 74 g/L; this concentration changes very little during the nursing period. Therefore, the amount of precursors necessary for lactose synthesis must increase. Lactose is synthe- sized from glucose and as a consequence, an increased supply of glucose must be obtained from ingested carbohydrate or from an increased supply of amino acids in order to prevent utilization of the lactating woman’s endogenous proteins. However, the amount of fat that can be oxidized daily greatly limits the contribution of glycerol to glucose production and thus lactose formation. For extended periods of power output exceeding this level, the dependence on carbohydrate as a fuel increases rapidly to near total dependence (Miller and Wolfe, 1999). Therefore, for such individuals there must be a corre- sponding increase in carbohydrate derived directly from carbohydrate- containing foods. Additional consumption of dietary protein may assist in meeting the need through gluconeogenesis, but it is unlikely to be con- sumed in amounts necessary to meet the individual’s need. A requirement for such individuals cannot be determined since the requirement for carbohydrate will depend on the particular energy expenditure for some defined period of time (Brooks and Mercier, 1994). They are composed of various proportions of glucose (dextrose), maltose, trisaccharides, and higher molecular-weight products including some starch itself. These syrups are also derived from cornstarch through the conversion of a portion of the glucose present in starch into fructose. Other sources of sugars include malt syrup, comprised largely of sucrose; honey, which resembles sucrose in its composition but is composed of individual glucose and fruc- tose molecules; and molasses, a by-product of table sugar production. With the introduction of high fructose corn sweeteners in 1967, the amount of “free” fructose in the diet of Americans has increased consider- ably (Hallfrisch, 1990). Department of Agriculture food consumption survey data, nondiet soft drinks were the leading source of added sugars in Americans’ diets, accounting for one-third of added sugars intake (Guthrie and Morton, 2000). This was followed by sugars and sweets (16 percent), sweetened grains (13 percent), fruit ades/drinks (10 percent), sweetened dairy (9 percent), and breakfast cereals and other grains (10 percent). Together, these foods and beverages accounted for 90 percent of Ameri- cans’ added sugars intake. Gibney and colleagues (1995) reported that dairy foods contributed 31 percent of the total sugar intakes in children, and fruits contributed 17 percent of the sugars for all ages. The majority of carbohydrate occurs as starch in corn, tapioca, flour, cereals, popcorn, pasta, rice, potatoes, and crackers. Between 10 and 25 percent of adults consumed less than 45 percent of energy from carbohydrate. Less than 5 percent of adults consumed more than 65 percent of energy from carbohydrate (Appendix Table E-3). Median carbohydrate intakes of Canadian men and women during 1990 to 1997 ranged from approximately 47 to 50 percent of energy intake (Appendix Table F-2).

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These receptors were known to send signals that promote cellular proliferation and survival discount nizagara 25mg with visa erectile dysfunction on coke, and increased signaling was thought to contribute to some cancers order nizagara 25mg without prescription erectile dysfunction age 18. However, the dramatic tumor shrinkage in some patients was enough for Food and Drug Administration approval in 2003, even though the molecular basis for the response was then unknown. Without the ability to recognize the responding patients as a biologically distinct subset, these agents were tried unsuccessfully on a broad range of lung-cancer patients, doing nothing for most patients other than increasing costs and side effects. In retrospect, some clinical trials with these agents probably failed because the actual responders represented too small a proportion of the patients in the trials (Pao and Miller 2005). This made it possible to predict which patients would respond to the therapy and to administer the therapy only to this subset of patients. This led to the design of much more effective clinical trials as well as reduced treatment costs and increased treatment effectiveness. Since then, many studies have further divided lung cancers into subsets that can be defined by driver mutations. Not all of these driver mutations can currently be targeted with drugs and cancer cells are quick to develop resistance to targeted drugs even when they are available. Nonetheless, this new information makes it possible to develop new targeted therapies that can extend and improve the quality of life for cancer patients. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 24 Source: Pao and Girard 2011 Figure 2-2: Knowledge of non-small-cell lung cancer has evolved substantially in recent decades. The traditional characterization of lung cancers based on histology has been replaced over the past 20 years by classifications based on driver mutations. However, the sophistication of this system for molecular classification has improved with the advent of more genetic information and the identification of many more driver mutations. Similar approaches could improve the diagnosis, classification, and treatment of many other diseases. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 25 The Urgent Need to Better Understand Phenotype-Genotype Correlations While dramatic progress in understanding the relationship between molecular features and phenotype is being made, there is an urgent need to understand these links better and to develop strategies to deal with their implications for athe individual patient. Of these, 1,167 were judged by the database’s curators as likely to be clinically significant, while most of the rest were categorized as of “unknown” clinical significance. Among the mutations that are believed to be clinically significant, some are thought to confer a higher risk of cancer than others (Gayther et al. To what extent does their mutation increase their risks of breast and ovarian cancer and how do these risks change with age? All of these real-life decisions carry heavy personal consequences as well as implications for health care costs. These treatment decisions do not need to be made based on such fragmentary information. It would be possible to assess the extent to which prophylactic surgeries reduced risk. It would be possible to assess the effectiveness of increased cancer screening, the best ways to screen these patients, and the complications that arise from the inevitable false-positive results that come from increased screening. Efforts along these lines have so far been based on modest numbers of patients or cohorts that are not fully representative of the larger population because it has not been practical to integrate genetic information, treatment decisions, and outcomes data for large numbers of unselected patients. However, recent advances in genomic and information technologies now make it possible to systematically address these issues by integrating large data sets that already exist. Even if only a subset of this variation has significant implications for disease risk or treatment response we have the potential to improve the detection, diagnosis, and treatment of disease dramatically by large-scale efforts to assess phenotype-genotype correlations. By integrating patient genotype with health information and outcomes data a New Taxonomy could identify many new genetic variants with significant implications for health care. There is every reason to expect that the genetic influences on most common diseases will be complex. In each patient, variants in multiple genes will affect disease onset, progression, and response to treatment, and long-term environmental modulation of these processes will be the rule rather than the exception. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 26 advances in our ability to understand epigenetic, environmental, microbial, and social contributions to disease risk and progression. Under these circumstances, there is an obvious need to categorize diseases with finer granularity, greater reference to the underlying biology, and in the context of a dynamic Knowledge Network that has the capacity to integrate the new information on many levels. Unraveling these diverse influences on human diseases will be a major scientific challenge of the 21st century. Prospective studies are particularly valuable because the occurrence or treatment of disease may alter the levels of the biochemical factors so that inference based on levels measured in a series of already diagnosed cases may be biased. These biomarkers can be combined with information on lifestyle risk factors such as smoking and body mass index, and measurements that may also change after diagnosis such as blood pressure, to create a risk score such as the Framingham Risk Score, that is widely used to predict the 10-year risk of heart attack (Anderson et al. Larger prospective cohort studies such as the Nurses’ Health Study (Missmer et al. For less common diseases, Consortia are again needed as no single study will have enough cases. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 27 consent mechanisms could generate similar large longitudinal sample sets and data through the provision of regular medical care, rather than considering these as research studies external to the health systems. Patients in these groups could then be recruited to provide samples or have their discarded clinical samples analyzed for research. In either case, the result would be a rich clinical characterization of patients at low cost and with linkages to corresponding biological samples that can be used for molecular studies. Research questions could be addressed faster and at lower cost as compared to the current standard practice of designing large, labor-intensive prospective studies. Such a scan may show that the original association is either an epiphenomenon of another pathology or part of a broader pathotype (Loscalzo et al. This approach provides an opportunity to explore this broader range of pathological mechanisms across a variety of disease types, which is not possible in single phenotype studies. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 28 relationships between genotype and disease is limited by the granularity and precision of the current taxonomic system for disease. A knowledge-network-derived taxonomy that distinguishes diseases with different biological drivers would enhance the power of association studies to uncover new insights. First, patient data, obtained during the normal course of clinical care, has proven to be a valid source for replicating genome-phenome associations that previously had been reported only in carefully qualified research cohorts. Second, although the individual institutions initially thought that they had large enough effect sizes and odds ratios to be adequately powered, in most cases, the entire network was needed to determine genome-wide association. The ability to extract high-quality phenotypes from narrative text is essential along with codes, laboratory results, and medication histories to get high predictive values. Fourth, although the five electronic medical systems have widely varying structures, coding systems, user interfaces, and users, once validated at one site, the information transported across the network with almost no degradation of its specificity and precision. For instance, a particular challenge has been to achieve both meaningful data sharing and respect for patient privacy concerns, while adhering to applicable regulations and laws (Kho et al. Evidence is already accumulating that these alternative and “informal” sources of health care data, including information shared by individuals from ubiquitous technologies such as smart phones and social networks, can contribute significantly to collecting disease and health data (Brownstein et al. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 29 Many data sources exist outside of traditional health-care records that could be extremely useful in biomedical research and medical practice. Informal reports from large groups of people (also known as ‘crowd sourcing’), when properly filtered and refined, can produce data complementary to information from traditional sources.

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However order 50mg nizagara visa erectile dysfunction joliet, when using simple costs only buy nizagara 50 mg mastercard erectile dysfunction jelly, the cost of treating non-insured patients must be fac- tored into the accounting. It should be possible from reading the article’s methods to set up the same pro- gram in any comparable setting. This requires a full description of the process of setting up the program, the costs and effects of the program, and how these were measured. Typically two treatment options or treatment as opposed to non-treatment are considered in a cost- effectiveness analysis. Using treatments that are no longer in common use will give a biased result to the analysis. There should be hard evidence from well-done randomized clinical trials to show that the interven- tion is effective, and this should be explicitly stated. Where not previously done, a systematic review or meta-analysis should be performed as part of the anal- ysis. A cost-effectiveness analysis should not be done based on the assump- tion that because we can do something it is good. Does the analysis identify all the important and relevant costs and effects that could be important? Were credible measures selected for the costs and effects that were incorporated into the analysis? On the cost side this includes the actual costs of organization and setting up a program and continuing operations, addi- tional costs to patient and family, costs outside the health-care system like time lost from work and decreased productivity, and intangible costs such as loss of pleasure or loss of companionship. These costs must be compared for both doing the intervention program and not doing the program but doing the alternatives. On the effect side, the analysis should include “hard” clinical outcomes: mor- tality, morbidity, residual functional ability, quality of life and utility of life, and the effect on future resources. These include the availability of services and future costs of health care and other services incurred by extending life. For example, it may be fiscally better to allow people to continue to smoke since this will reduce their life span and save money on end-of-life care for those people who die prematurely. The error made most often in performing cost-effectiveness analyses is the omission of consideration of opportunity costs that were referred to at the start of this chapter. If you pay for one therapeutic intervention you may not be able to pay for some other one. Cost-effectiveness analyses must include an analysis of these opportunity costs so that the reader can see what equivalent types of programs might need to be cut from the health-care budget in order to finance the new and presumably better intervention. Analyses that do not consider this issue are giving a biased view of the usefulness of the new program and keeping it out of the context of the most good for the greater society. The marginal or incremental gain for both the costs and effects should be cal- culated. This is the number of patients you must treat in order to achieve the desired effect in one additional patient. This is com- pared to the marginal cost of the better treatment to get a cost-effectiveness estimate. The marginal or incremental cost per life saved is then $180 000 [($2000 − $200) × 100 lives]. Also, the effects measured should include lives or years of life saved, improvement in level of function, or utility of the outcome for the patient. This works if the effects of the two interventions are equal or minimally different. For example, when compar- ing inpatient vein stripping to outpatient injection of varicose veins, the results shown in Table 31. Here the cost is so different that even if 13% of outpatients require additional hospitalization (and therefore we must pay for Cost-effectiveness analysis 355 Table 31. Comparing doxycycline to azithromycin for Chlamydia infections Treatment Outcomes Cost to hospital No further Adverse Compliance per patient treatement needed effects rate Doxycycline 3 77% 29% 70% Azithromycin 30 81% 23% 100% Source: Data extracted from A. The cost effective- ness of azithromycin for Chlamydia trachomatis infections in women. Another analysis compared doxycycline 100 mg twice a day for 7 days to azithromycin 1 g given as a one-time dose for the treatment of Chlamydia infec- tions in women. It found that some patients do not complete the full 7-day course for doxycycline and then need to be retreated, and can infect other people during that period of time (Table 31. The cost of azithromycin that would make the use of this drug cost-effective for all patients can then be calculated. In this case, the drug company making azithromycin actually lowered their price for the drug by over 50% based on that analysis, to a level that would make azithromycin more cost-effective. In a cost-effectiveness analysis the researcher seeks to determine how much more has to be paid in order to achieve a benefit of preventing death or dis- ability time. The first step in a cost-effectiveness analysis is to determine the difference in the benefits or effects of the two treatment strategies or policies being compared. This is done using an Expected Values Decision Analysis as described in Chapter 30. It is possible that one of the tested strategies may have a relatively small benefit and yet be overall more cost-effective than others therapies, which although only slightly less effective are very much more expensive. Next the difference in cost of the two treatment strategies or policies must be determined, to get the incremental or marginal cost. The cost-effectiveness is the ratio of the incremental cost to the incremental gain. The cost- effectiveness of B as compared to A is the difference in cost divided by the dif- ference in effects. Note that if the more effective treatment had also cost less, you should obviously use the more effective one unless it has other serious drawbacks such as serious known side effects. Calculate this only when the more effective treatment strat- egy or policy is also more costly. Are the conclusions unlikely to change with sensible changes in costs and outcomes? Since most research on a given therapy is done at different times, changes over time must be accounted for. It takes into account that inflation occurs and that, instead of paying for a program now, those costs can be invested now and other funds used to pay for solving the problem later. The future costs are usually expressed in current dollars since $200 in the future is equivalent to less than $200 today. Actu- arial and accounting methods used should be specified in the methods section of the analysis. Setting up a program is usually a greater cost than running it and initial costs are usually amortized over several decades. Discounting the value side of the equation considers that the value of a year of life saved now may be greater than a year saved later. Adding a year of life to someone at age 40 may mean more to them than adding a year of life to a 40-year-old but only after they reach the age of 60. This was considered in the discussion on patient preferences and values in Chapter 30. As with any other clinical research study, the numbers used to perform the analysis are only approximations and have 95% confidence levels attached.

Migraine Classical migraine has an aura (a prodrome of symptoms such as flashing lights) lasting up to an hour preceding the onset of pain generic nizagara 50mg visa erectile dysfunction medications cost, frequently accompanied by nausea and vomiting discount nizagara 25 mg overnight delivery erectile dysfunction pills online. The headache is often localised, becoming generalised and persists for several hours. Cervical spondylosis Pain in the suboccipital region associated with head posture and local tenderness relieved by neck support. Temporal arteritis Severe headache and scalp tenderness over the inflamed, palpably thickened superficial temporal arteries with progressive loss of the pulse. In both types sociated with paraesthesia, numbness, cramps and motion, particularly of the head, can exacerbate the sen- tetany. With a chronic lesion such as a tumour, adaptive Hysteria may lead to non-epileptic attacks (pseudo- mechanisms reduce the sensation of dizziness over a pe- seizures) with or without feigned loss of consciousness. The patient will drop to the ground in front of witnesses, withoutsustaininganyinjuryandhaveafluctuatinglevel Labyrinth disorders (peripheral lesions) of consciousness for some time with unusual seizure- Peripherallesionstendtocauseaunidirectionalhorizon- like movements such as pelvic thrusting and forced eye tal nystagmus enhanced by asking the patient to look in closure. This is a diagnosis they tend to veer to one side, but walking is generally of exclusion and should be made with caution. Symptoms last days to weeks and can be is the sensation experienced when getting off a round- reduced with vestibular sedatives (useful only in the about and as part of alcohol intoxication. Positional testing with the Hallpike appears after a few seconds (latency), lasts less than manoeuvre is diagnostic. It tient’seyesarecloselyobservedfornystagmusforupto responds poorly to vestibular sedatives. This test can Central lesions provoke intense nausea, vertigo and even vomiting, Acentral lesion due to disease of the brainstem, cere- particularly in peripheral lesions. For ex- ample, risk factors for cerebrovascular disease, previous history of migraine, demyelination, or the presence of any other neurology. Altered sensation or weakness in the limbs Altered sensation in the limbs is often described as numbness, pins and needles (‘paraesthesiae’), cold or hot sensations. Painful or unpleasant sensations may be felt, such as shooting pains, burning pain, or increased sensitivity to touch (dysaesthesia). There may be a pre- cipitating cause, such as after trauma, or exacerbating features. The distribution of the sensory symptoms, and any associated pain (such as radicular pain, back pain or neck pain) can help to determine the cause. Depending on the level of the lesion the weak- r Can you get up from a chair easily? Signs to use your arms to help you get up from a include: chair or to climb up stairs? Glove and stocking sensory loss in all modalities (pain, temperature, vibration and joint position sense) occurs in peripheral neuropathies. They may have peripheral muscle weakness, which is also bilateral, symmetrical and distal. Bilateral symmetrical loss of all modalities of sensation occurs with a transverse section of the cord. These lesions are characteristically associated with lower motor neurone signs at the level of transection and upper motor neurone signs below the level. There are also ipsilateral upper motor neurone signs below the level of the lesion and lower motor neurone signs at the level of the lesion. Depending on the severity, the weakness may be de- r Anterior horn cell lesions occur as part of motor neu- scribed as a ‘plegia’ = total paralysis, or a ‘paresis’ = rone disease, polio or other viral infections, and can partial paralysis, but these terms are often used inter- affect multiple levels. Common causes are st- will cause weakness and wasting of the small muscles rokes(vascularocclusionorhaemorrhage)andtumours. Ask the patient to say r Decreased power in the distribution of the affected ‘British Constitution’ or ‘West Register Street’. Usually due to a cervical spinal cord lesion, occasionally bilateral cerebral lesions. Hemiplegia Weakness of one half of the body (sometimes including the face) caused be a contralateral cerebral hemisphere lesion, a brainstem lesion or ipsilateral spinal cord lesion (unusual). Paraplegia Affecting both lower limbs, and usually caused by a thoracic or lumbar spinal cord lesion e. Bilateral hemisphere (anterior cerebral artery) lesions can cause this but are rare. Monoplegia Contralateral hemisphere lesion in the motor cortex causing weakness of one limb, usually the arm. Test the abil- r Bradykinesia (slowness in movements) is noticeable ity of the patient to sit on the edge of the bed with their when doing alternate hand tapping movements, or arms crossed. Micro- r Gait:Wide-basedgait,withatendencytodrifttowards graphia (small, spidery handwriting). Even a mild cerebellar problem makes tiation of movement is impaired (hesitancy) with the this very difficult. A festinating gait is Causes include the following: r when the patient looks as though they are shuffling in Multiple sclerosis r order to keep up with their centre of gravity, and then Trauma r has difficulty in stopping and turning round. The three groups of tremor are distinguished by obser- r Metabolic: Alcohol (acute, reversible or chronic de- vation (see Table 7. If unilateral, the leg is swung out to the side to move it forwards (circumduction). If bilateral, the Extrapyramidal signs (Parkinsonism) pelvis has to alternately tilt and the gait often becomes r Appearance: Expressionless face. Thepatientcanstandontip-toe,butoften Resting tremor which is slow and classically pill- not on their heels. Even if mildly affected the patient is unable to strating whether seizure activity is suppressed by walk heel-toe in a straight line. In or encephalitis, as well as occurring in focal status Parkinson’s disease, this pattern tends to be asym- epilepticus. They are useful in the di- agnosis of muscle disease, diseases of the neuromuscular Electroencephalography junction, peripheral neuropathies and anterior horn cell disease. It is obtained by placing electrodes on the scalp, using a jelly to reduce electrical Electromyography resistance. A recording of at least half an hour is usually Aneedleelectrodeisplacedintomusclesandinsertional, needed, to maximise the chances of picking up tran- resting and voluntary electrical activity is studied, using sient abnormalities. Its main use is for the classification of epilepsy, but is r Peripheral neuropathies and anterior horn cell disease it may also be useful in the diagnosis of other brain dis- lead to a reduced number of motor units, which fire orders such as encephalitis. Surface electrodes or occasionally needles are used both r Suspected spinal cord compression. The knees are drawn up as far as possible and uation of brachial and lumbosacral plexus and nerve the neck flexed, to open up the spinous processes of the roots. The lumbar puncture needle is inserted in the midline Lumbar puncture with its stylet in place aiming slightly towards the um- bilicus. If the needle encounters firm resistance, it Indications should be withdrawn and another approach tried. When any of the following are suspected: Sometimes the patient will feel a pain radiating into r Infection (meningitis, encephalitis, fungal infections the leg or back – this is due to the needle touching a or neurosyphilis).

Their knowledge was based on a biological technology that was already thousands of years old – fermentation Terms by yeast buy nizagara overnight delivery strongest erectile dysfunction pills. Biopharmaceuticals drugs manufactured using biotech- Though it may sound nological methods buy cheap nizagara 50 mg erectile dysfunction blood flow. The only thing that is relatively new about the biotechnology industry is its name. Stone Age, Iron Age, The term ‘biotechnology’ was first used in a 1919 Age of Biochemistry publication by Karl Ereky, a Hungarian engineer and economist. He foresaw an age of biochemis- try that would be comparable to the Stone Age and the Iron Age in terms of its historical significance. For him, science was part of an all-embracing economic theory: in combination with po- litical measures such as land reform, the new techniques would provide adequate food for the rapidly growing world population – an approach that is just as relevant today as it was in the pe- riod after the First World War. Until well into the second half of the 20th century biologists worked in essentially the same way as their Babylo- Beer for Babylon 9 1665 C. Two years later Antoni van Leeuwenhoek becomes the first person to see bacterial cells. Thanks to newly developed methods, however, the biotechnol- ogy of the 20th century was able to produce a far greater range of such natural products and at far higher levels of purity and quality. This was due to a series of discoveries that permit- ted the increasingly rapid development of new scientific tech- niques: T In the first half of the 19th century scientists discovered the basic chemical properties of proteins and isolated the first enzymes. Over the following decades the role of these sub- stances as biological catalysts was elucidated and exploited for research and development. T The development of ever more sophisticated microscopes rendered the form and contents of cells visible and showed the importance of cells as the smallest units of life on Earth. Louis Pasteur postulated the existence of microorganisms and believed them to be responsible for most of the fermen- tation processes that had been known for thousands of years. T From 1859 Charles Darwin’s theory of evolution revolution- ised biology and set in train a social movement that led ul- timately to a new perception of mankind. For the first time the common features of and differences between the Earth’s organisms could be explained in biological terms. As a result, biology changed from a descriptive to a more experimental scientific discipline. T The rediscovery of the works of Gregor Mendel at the end of the 19th century ushered in the age of classical genetics. Cultivation and breeding techniques that had been used for thousands of years now had a scien- tific foundation and could be further developed. It will be white blood cells in purulent 35 years before his work receives the bandages that he refers to as ‘nuclein’. In addition to the classical, mostly agricultural, products, more and more new products entered the market- place. Enzymes were isolated in highly purified form and made available for a wide variety of tasks, from producing washing powder to measuring blood glucose. Standardised biochemical test methods made their entrance into medical diagnostics and for the first time provided physicians with molecular measuring instruments. The structures and actions of many biomolecules were elucidated and the biochemical foundations of life thereby made more transparent. Gene technology spurs However,it was only with the advent of gene tech- innovation nology that biology and biotechnology really took off. Desired changes in the genetic makeup of a species that previously would have required decades of system- atic breeding and selection could now be induced within a few months. For example, newly developed techniques made it possible to in- sert foreign genes into an organism. This opened up the revolu- tionary possibility of industrial-scale production of medically important biomolecules of whatever origin from bacterial cells. The first medicine to be produced in this way was the hormone insulin: in the late 1970s Genentech, an American company, de- veloped a technique for producing human insulin in bacterial cells and licensed the technique to the pharmaceutical company Eli Lilly. Gene technology: human insulin from bacteria In 1982 human insulin became the world’s first biotechnolog- In 1978 the biotech company Genentech developed a method ically manufactured medicine. These were then separately isolated, combined and betes and most people with type 2 diabetes require regular finally converted enzymatically into active insulin. In its day, this classical biotechnological method it- Some 200 million diabetics worldwide now benefit from the self represented a major medical breakthrough: until 1922, production of human insulin. Without gene technology and when medical scientists discovered the effect of pancreatic biotechnology this would be impossible: in order to meet cur- extracts, a diagnosis of type 1 diabetes was tantamount to a rent demands using pancreatic extract, around 20 billion pigs death sentence. A new economic This technology laid the foundation for a new in- sector arises dustry. The early start-up biotech companies joined forces with large, established pharmaceu- tical companies; these in turn used biotechnology to develop high-molecular-weight medicines. Rapid expansion In the early 1980s very few companies recognised and stock market boom the medical potential of the rapidly expanding field of biotechnology. This company, which can lay claim to being a founder of the modern biotech industry, was formed in 1976 by Herbert Boyer, a scientist, and Robert Swanson, an en- trepreneur, at a time when biochemistry was still firmly ground- ed in basic research. This was true both in relation to sales and number of companies and also in relation to public profile. The situation changed abruptly, however, when biotech prod- ucts achieved their first commercial successes. In the 1990s pro- gress in gene technological and biotechnological research and development led to a veritable boom in the biotech sector. Within a few years thousands of new biotech companies sprang up all over the world. Fuelled by expectations of enormous future profits, the burgeoning biotechnology indus- try became, together with information technology, one of the driving forces behind the stock market boom of the final years of the 20th century. Measured on the basis of their stock market value alone, many young biotech companies with a couple of dozen em- ployees were worth more at that time than some estab- lished drug companies with annual sales running into hundred of millions of dollars. While this ‘investor exuberance’ was no doubt excessive, it was also essen- tial for most of the start-ups that benefited from it. For This life-size bronze sculpture of Genentech’s founders the development of a new is on display at the company’s research centre in South drug up to the regulatory San Francisco. The main reason for this is the high proportion of failures: only one in every 100,000 to 200,000 chemically synthesised molecules makes it all the way from the test tube to the pharmacy. Biotechnological production permits the manufacture of com- plex molecules that have a better chance of making it to the mar- ket. On the other hand, biotechnological production of drugs is more technically demanding and consequently more expensive than simple chemical synthesis. Without the money generated by this stock market success, scarcely any young biotech com- pany could have shouldered these financial risks. The first modern biotechnology company: Genentech It took courage to found a biotechnology company in 1976.

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They wish to be given suf- treating a 62-year-old widow with carcinoma of the colon buy discount nizagara 50 mg on line erectile dysfunction statistics race. They The resident carried out the surgical procedure with the expect patients to accept some responsibility for their own assistance of the attending surgeon nizagara 50 mg low price erectile dysfunction joliet. Canadian physicians want their health care system to be the resident and regards the resident as her surgeon. The equitable, adequately funded and staffed, and to afford reason- patient is aware of the diagnosis and understands that able professional freedom. She lives alone there is a balance between the practice of medicine, family and and wants her family to participate in the discussion about other interests. Finally, they expect reasonable rewards, both treatment options before her discharge. The For their part, residents must cope with the expectations of resident has been on call since the night before, is required their mentors, the institution within which they work, and by the residents’ contract to be off-duty, and the family their training program. In Canada, the broad outline of these has tickets to a hockey game with their son as a birthday expectations is documented in a contract. For Introduction example, it is inconceivable that a resident would leave a care Professionalism has been described as the basis of medicine’s setting at the end of a shift when to do so would put a patient’s social contract with society. However, one of the major objectives of limiting members are granted the privilege of autonomy in practice, a time on call is to protect the health of the resident, ultimately monopoly over the practice of medicine through licensure, the for the sake of patients—it is well documented that the judg- right to physician-led regulation, and both fnancial and nonf- ment of a tired or overstressed resident or physician can be nancial rewards. The most signifcant tension that This “bargain” with society leads to tangible expectations on may arise stems from a confict between altruism—a sense of the part of patients and society on one side and on the part of obligation to put patients’ needs above one’s own—and the physicians and the profession on the other. In contem- all of the obligations expected of physicians in a complex and porary Canada, this tension is exacerbated by a real shortage of frequently underfunded and understaffed health care system physicians and other health care professionals, which has led often places impossible demands on individual physicians. No one likes to see others go without access to a physician or endure long waits for treatment. Thus, each resident and practising physician constantly balances the needs of individual patients and of society with their own personal well-being. One must often look for the “least-worst” path in trying Physician-led regulation requires each individual physician to to meet the legitimate expectations of one’s patients and accept responsibility for the competence and behaviour of his one’s self. However, if the or unethical conduct on the part of another resident or prac- resident in this case example stays to meet with the family, titioner must take appropriate action. It is the responsibility they will violate the terms of the resident contract and of the training program to have well-publicized processes to disappoint their own family. It is essential that these processes ensure that no be diffcult; enlisting the help of the attending surgeon, harm to the resident’s career follows from the disclosure of who has the primary fduciary responsibility in this case; or unacceptable conduct on the part of others. There are times when one’s responsibility ate training and continues throughout professional life. It is to patients must take precedence over family needs or a process of socialization during which individuals begin as contractual obligations. Compromise is certainly accept- uninitiated members of the lay public and gradually acquire able on occasion, and for good reason. This happens in parallel frst” becomes a pattern of behaviour, the health of the with the transformation from non-expert to expert clinician. This issue In recognition of this, there are different expectations for phy- must be addressed openly during training. As stu- fact that limits must be placed on the expectations of all dents and residents accept increasing levels of responsibility parties to the social contract. Expectations and obligations: situations that arise, and that they can make the often diffcult professionalism and medicine’s social contract with society. Training programs bear a heavy responsibility in ensuring that unreasonable demands are not chronically imposed upon residents, and that tensions concerning professional versus personal priorities are discussed openly throughout a resident’s training. Behavioural patterns that are detrimental to a healthy lifestyle are often set during residency training. On a more positive note, being aware of the tensions that inevitably arise in practice, and having an opportunity to refect on them in a supportive environment, can help to establish patterns of behaviour that both preserve the professionalism of medicine and lead to healthy patterns of living. The impact of long duty hours Working around the clock can be socially, physically and psy- Case chologically challenging. Long duty hours can lead to isolation A frst-year resident feels life is like a runaway train. They from friends and support networks, straining relationships and feel tired and irritable all the time, and their world is over- preventing physicians from maintaining former activities and fowing with medicine (facts, patients, readings, rounds, connections. Extensive time at work can tax one’s energy and procedures, test results, assignments and call). The resident lead to irritability, depressed mood, substance abuse and other misses their family, cooking a good meal, and having time mental health problems. They can’t re- around the clock are a risk factor for weight gain, immune dys- member their last workout. The resident could use a good function, infertility, diabetes, gastrointestinal complaints and night of sleep, too, but they are on call again tonight and coronary artery disease. The resident is starting duty hours such as years of shiftwork involving night shifts to fnd patients and their complaints annoying. When they and sleep loss have been equated with smoking a pack of ciga- observe their supervisor they are working with today, the rettes per day. Working outside of regular business hours, as in resident notices the supervisor looks just as tired. The doing call or shiftwork, disrupts the circadian rhythms critical resident wonders if they are cut out for medicine. Introduction That medical practice is characterized by intense and long Work hours and fatigue work hours is an understatement. Patients do not choose the Traditionally, fatigue was thought to be a simple equation: fa- hour they become ill, and twenty-frst century medicine is a tigue = hours of work. Physician shortages, an aging population, fatigues one person one day might not have the same impact and diffculties accessing health care mean that the patients on someone else, or even on the same person in other circum- physicians see have increasingly complex needs and are sicker. Fatigue is perhaps better thought of as a function of The exponential growth in medical knowledge and technology an interaction of different factors (see textbox): the individual also place greater demands on physicians, and physicians-in- (e. In the 2007 Canadian National Physician Survey, work, and this can lead to inattention or medical error, putting the mean reported time spent on professional duties, before patients at risk (Crosskerry 2008). Over the longer term, physi- call, was about 51 hours per week across all specialties, practices cian fatigue can lead to mental or physical health problems, and ages. Sixty-one percent of physicians also reported work- burnout, and exit from practice. Physicians-in-training, with Strategies to cope with long work hours a few short years to prepare for practice, typically spend 60, 80 What can a physician do to mitigate the effects of long work or more hours on duty every week, depending on the specialty hours? These long hours of duty put physicians numbers of physicians, and cures for diseases, medicine will at risk for a number of negative consequences.

They agree that physicians feel that their medical careers are important order nizagara 50 mg with amex erectile dysfunction kegel, they any threat to their professional standards or that of a hospital “do not necessarily place [their work] at the forefront as the is potentially stressful and can affect their relationship with pa- only aspect of who they are order nizagara 50mg visa erectile dysfunction otc. A culture of openness can help to mitigate these threats, younger cohort seeks a well-rounded and balanced life can be and a healthy sense of community among the physicians can interpreted by baby boomers as a lack of commitment (Jovic help physicians to cope with stressful situations. Bill Wilkerson, co-founder of the Global Business and The number of female physicians has increased 36. In the 2007 National Physician Survey, 80 per cent of physi- What is the solution in the workplace? Wilkerson puts it this cians indicated that the complexity of their patient caseload as way: “The solution is the cornerstone of good old-fashioned the biggest factor affecting their time. Given an ever-increasing management, which is based on human decency, clear think- proportion of our aging population is affected by chronic dis- ing, open communications. The other cornerstone is clarity of ease and comorbidities, the average physician’s workload will purpose and function. CanadianMedicalAssociation Of the medical students who responded to the 2007 National Launches First Check-up of Doctors’ Health. Society grants physicians status, respect, autonomy in practice, ability to self-regulate and fnan- cial compensation. In return, society has high expectations of Case physicians, including competence, altruism, ethical behaviour A physician is ill and chooses to take a day off from his and the delivery of a high standard of care. A number of patient visits are professional role physicians must make their patients’ well- rescheduled, and students and residents are assigned to being their frst priority, this commitment must include a caveat other supervisors. Physicians should bear in mind the advice ents the following week but begins the clinical encounter given to airline passengers in case of a depressurization: put by expressing dissatisfaction, anger and frustration that on one’s own oxygen mask before assisting others. We must the postponement of the appointment resulted in losing maintain our own health in order to be ft to care for society. The physician feels regretful and guilty at having taken the day off, but at the same time is frustrated by the patient’s demanding tone. Refection for educators At the beginning of your residents’ rotation, have them keep a journal of the challenges they encounter with Introduction respect to meeting the expectations of their patients and Society is quite aware of basic lifestyle choices that promote maintaining their own health. You may wish to provide good health, such as maintaining a healthy diet, exercising your own example of challenges you have experienced. In regularly, avoiding smoking and street drugs, and limiting addition, you can keep your own journal of such physician alcohol use. Most Canadians also recognize the importance of health challenges and have a formal discussion half-way working with their primary care physician for health concerns, through the rotation on how you and your residents dealt follow-up and appropriate screening at different stages of life. At their regular evaluation However, how often do patients consider the health needs of meetings program directors can discuss with residents the their own doctors? The journal will provide clear examples of how the residents understand Healthy physician, healthy patient the key issue. Residents may also consider incorporating Some patients infuence the mental health of their physicians such discussions into their half-day educational sessions by virtue of challenging personality traits, the denial of their or at their regular retreats. Physicians may choose to prescribe unneces- sary antibiotics for a viral illness to pacify the expectations of a patient who wants a quick resolution of their ailment. However, while these physicians are well aware of the lack of effcacy of antibiotics in these situations and the potential to promote new strains of resistant bacteria, they may feel they lack the time or energy to go through the process of proper patient education. The evolution of medicine into the computer era has also contributed to the complexity of the physician–patient relationship where physician health is concerned. Although one rarely hears of a house calls nowadays, e-mail is today’s equivalent of yesterday’s housecall. Patients can now follow doctors home, on vacation, or literally anywhere technology may go. What about the concept that patients need to be seen in person for a physician to make clinically informed deci- sions about their care? Today’s society expects medicine to be a convenient service, similar to the fast-food industry—which likely contributed to the development of the walk-in clinic. The patient appreciates the bedside: social expectations and value triage in medical practice. Many of these elements can readily contribute acknowledge that individual physicians have an opportunity to personal health and sustainability. Thus, in the last chapter to identify and develop their skills in a several critical areas, of this section, readers are encouraged to consider practical namely personal awareness (described as values, beliefs and suggestions to guide the development of their own leadership knowledge), refective practice, emotional intelligence and skills. Emerging evidence suggests that the development readers can readily access to enhance their understanding and of skills in each of these areas is associated with improved practise of leadership. There is no doubt that many other facets of health and sus- Personal awareness tainability are of relevance to physicians. Starting with the perspective of search for information and practical ways to move forward Mahatma Gandhi, it considers what is meant by “values,” “be- with your own personal health and professional sustainability liefs” and “knowledge. Through exercises and refec- Key references tion, readers will have an opportunity to consider how best www. Interactive and practical, it includes sections on relationships, depression and anxiety, resiliency, substance Refective practice use, personal care and many other issues. Other professions and disciplines have long valued self- assessment, critical appraisal of the self, and introspection. Offering interactive exercises enhance professional development, improve personal health, focused on the development of insight and skills, it blends and promote patient care. The second chapter in this section many of the skills of this section of the guide and offers prac- introduces the basic principles of refective practice, offering a tical methods to enhance the health care workplace. Referring to the work of thinkers such as Howard Gardiner, Peter Salovey, John Mayer and Daniel Goleman, the third chapter in this section suggests that models of emotional intel- ligence have much to offer the medical profession. Readers will be encouraged to consider several recommendations from the literature on emotional intelligence and will be challenged to assess and build on their strengths in this area. At the level of the individual, value systems arise • discuss the infuence of values and beliefs on physicians’ primarily from familial circumstance and early life experience. They are • describe modes of self-refection on personal health and deeply engrained, a core part of our identity, and central to our wellness. Debates based solely on values often result in a stalemate, as neither side, despite an exchange Case of perspectives and information is able to change. A bright and clinically talented fellow has taken on many leadership roles and positions. One night, the fellow’s Refection spouse of four years asks for some time to talk. The fellow Identify six to eight roles that you have in your life at pres- is shocked to learn that their spouse feels lonely in their ent (e. The spouse asks for a period of separation so time that you dedicate to each of these roles. Rank your they can both consider how they want their marriage to success in each role on a scale (0 = complete failure, 5 = move forward (or not).