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Macroscopy The tumour is usually a polypoid mass on a stalk discount atorvastatin 20mg mastercard, its sur- Microscopy face covered with thrombus generic atorvastatin 20 mg visa. It is composed of is made up of connective tissue purchase atorvastatin 20 mg without prescription, with a variety of cell chief cells with clear cytoplasm and a round nucleus en- typessurrounded by extracellular matrix. Investigations Management Angiography shows a splaying of the carotid bifurcation The tumour is surgically removed under cardiopul- (lyre sign). Management Prognosis Surgical excision may be performed especially in young Five per cent local recurrence within 5 years. Inelderlypatientssurgicalremovalmay up with regular echocardiography is therefore indicated not be necessary. Patients may complain of breathlessness, dif- ficulty in ‘catching their breath’, a feeling of suffocation, Cough and sputum or tightness in the chest. Dyspnoea should be graded by the exertional capability of the patient and the impact Acough is one of the most common presentations of on their lifestyle. In general dyspnoea arises from either the respira- The most common patterns are shown in Table 3. It is usu- thopnoea and paroxysmal nocturnal dyspnoea suggests ally streaky, rusty coloured and mixed with sputum. It a cardiovascular cause, patients with lung disease may should be distinguished from haematemesis (vomiting experience orthopnoea due to abdominal contents re- of blood) which may appear bright red or like coffee stricting the movement of the diaphragm. For diagnosis, respiratory dyspnoea is best considered 1 The most common cause is acute infection, particu- according to the speed of onset and further differenti- larly with underlying chronic obstructive airways dis- ated by a detailed history and clinical examination (see ease. Wheeze and stridor 3 Pulmonary oedema in cardiac failure causes pink, frothy sputum and pulmonary infarction such as pul- Wheeze and stridor are respiratory sounds caused by air- monary embolism may cause haemoptysis. Massive haemoptysis may be caused by bronchiectasis, Awheeze is described according to where it is best bronchial carcinoma or tuberculosis. Recent Smoker, weight Haemoptysis Carcinoma until proved (weeks) loss, occasionally otherwise (often dull chest pain associated pneumonia) specific size of airway – usually one bronchus) or poly- creased airway pressure opens the valve, so expiratory phonic (widespread airway limitation). Othercauses inhalation, acute epiglottitis (drooling, unwell), ana- include chronic obstructive airways disease and acute phylaxis, inhaled foreign body. It occurs airway (larynx, pharynx or trachea), extrinsic com- because in inspiration, a valve-like effect worsens ob- pression (lymph nodes, retrosternal thyroid), bilateral struction in the major airways. Pulmonary oedema Cardiac history, intermittent (exertional, orthopnoea, paroxysmal nocturnal dyspnoea) or acute – basal crackles, frothy sputum, cardiac chest pain Extrinsic allergic alveolitis Recurrent, occupational exposure Days/weeks Pleural effusions Dull to percussion, reduced breath sounds Carcinoma of the bronchus/ Obstruction causes collapse and consolidation of lung. Months/years Chronic bronchitis/emphysema Smoking history, cough & sputum Idiopathic pulmonary fibrosis Clubbing and cyanosis, fine crackles Occupational fibrotic lung disease Occupational history 92 Chapter 3: Respiratory system Respiratory chest pain with abdominal pain, e. Chest pain can arise from the cardiovascular system, the respiratory system, the oesophagus or the musculoskele- talsystem. Respiratorychestpainisusuallyverydifferent Signs fromischaemicchestpain,asitischaracteristicallysharp, and worse on inspiration. Clubbing On enquiring about chest pain ask about the site, nature (sharp, burning, tearing), radiation, precipitat- Clubbing is an increased amount of soft tissue in the ing/relieving factors (deep inspiration, coughing, move- terminal phalanx of the fingers and toes, concentrated ment) and any associated symptoms such as dyspnoea. It is caused by inflamed pleural pathological mechanism of clubbing is unknown, and surfaces rubbing on one another. Pleurisy may also be caused by connective tissue diseases such as rheumatoid Normal breath sounds are caused by the turbulent flow arthritis. They are Chest wall pain may be easily confused with pleuritic transmitted to the chest wall through the lungs (see pain, as it is often sharp, but it can be reproduced by Table 3. Other Bronchiectasis causes include thoracic herpes zoster – a persistent pain, Lung abscess which may be burning and last several days before the Chronic empyema Pulmonary fibrosis rash appears. Idiopathic pulmonary fibrosis Retrosternal pain may be due to tracheitis or medi- Cystic fibrosis astinal disease (lymphoma, mediastinitis) but is more Asbestosis commonly cardiac. Cardiovascular Cyanotic congenital heart disease Infective endocarditis Gastrointestinal Cirrhosis, especially primary biliary Non-respiratory chest pain cirrhosis Central chest pain, particularly if radiating to the neck Inflammatory bowel disease Coeliac disease or arms, is more likely to be cardiac. Pericarditis causes Idiopathic Familial usually before puberty a sharp retrosternal/precordial pain which may mimic Idiopathic pleuritic pain as it may be exacerbated by deep inspira- Rare Thyroid acropachy tion, but is classically relieved by leaning forwards. Pain Pregnancy at the shoulder tip is often referred pain from the di- Unilateral clubbing Bronchial arteriovenous aneurysm aphragm, and may reflect an abdominal cause such as Axillary artery aneurysm cholecystitis. Equally, respiratory disease may manifest Chapter 3: Respiratory procedures 93 Table3. Inspiration is However, theseconditionsmayoccurwithoutwheeze, slightly louder and longer than despite severe obstruction. Crackles/crepitations: Normally the airways do not col- Reduced Bilaterally: Chronic obstructive pulmonary disease, severe acute asthma. They are differentiated sounds from the larger airways better, so the whole of inspiration and by their timing and nature: r Early inspiratory crackles come from the airways, expiration are heard. These are divided into wheezes from the airways, crack- Pleuralfrictionrub:Acreaking sound in inspiration and les, which come from the large airways, the bronchioles expiration, localised over an area of pleural inflamma- and the alveoli, and friction rubs from the pleura (see tion. Wheezes are musical sounds caused by airway ob- struction and are usually heard in expiration. It is caused by bronchial carcinoma or inhaled foreign body, and is frequently inspiratory. The in obstructive airways disease, although both may be best of three tries is recorded.

Now add the patients lost to follow-up Survival analysis and studies of prognosis 361 Table 32 discount 10 mg atorvastatin fast delivery. A study of 71 patients 6 of whom were lost to follow-up Original study “Highest” case “Lowest” case Relapse rate 39/65 = 60% 45/71 = 63% 39/71 = 55% Mortality rate 1/65 = 1 cheap 5mg atorvastatin with mastercard. As a general rule discount 5mg atorvastatin with amex, the lower the rate of an outcome, the more likely it is to be affected by patients lost to follow-up. The intervention There should be a clear and easily reproducible description of the intervention being tested. The reader should be able to duplicate the process of the study at another institution. It is of paramount importance that the intervention proposed in the study be one that can be performed in settings other than at the most advanced tertiary care setting only. Similarly, testing a drug against placebo may not be as important or useful as testing it against the drug that is currently the most favorite for that indication. Most of these issues have been discussed in the chap- ter on randomized clinical trials in Chapter 15. The out- come assessment should also be done in a blinded manner to avoid diagnostic suspicion and expectation bias in the assessment of patient outcomes. There can be significant bias introduced into the study if the outcomes are not measured in a consistent manner. Death or life are clear and easily measured outcome variables although the cause of death as measured on a death certificate is not always a reliable, clear, or objective outcome measure of the actual cause of death. Admission to the hospital appears to be clear and objective, but the reasons or threshold for admission to the hospital may be very subjective and subject to significant inter- rater variability. Outcomes such as “full recovery at home” or “feeling better” have a higher degree of subjectivity associated with them. The researcher should determine whether the prognostic factor is merely a marker or actually a factor that is responsible for the causation. This determines whether or not there are alternative explanations for the outcomes due to some confounding variable. Count on the article being reviewed by a statistician who can determine if the authors used the correct statistical analysis, but be aware that the correct adjustment for extraneous factors may not have been done correctly if at all. If the authors suggest that a group of signs, symptoms, or diagnostic tests accu- rately predict an outcome, look for a validation sample in a second study which attempts to verify that indeed these results occurred because of a causal rela- tionship and not just by chance. Look for at least 10 and preferably 20 patients who actually had the outcome of interest for each prognostic factor that is eval- uated to give clinically and statistically significant results. One is interested in the association of an inde- pendent variable such as drug use, therapy, risk factor, diagnostic test result, tumor stage, age of patient, or blood pressure with the dependent or outcome variable. Diagnostic-suspicion bias occurs when the physician caring for the patient knows the nature and purpose of the outcomes being measured and as a result, changes the interpretation of a diagnostic test, the actual care or observation of the patient. Expectation bias occurs when the person measuring the outcome knows the clinical features of the case or the results of a diagnostic test and alters their interpretation of the outcome event. This is less likely when the interven- tion and outcome measures are clearly objective. Ideally blind diagnosis, treat- ment, and assessment of all the patients going through the study will prevent these biases. Another problem in the outcomes selected occurs when multiple outcomes are lumped together. Many more studies of therapy are comparing two groups for several outcomes at once and these so-called composite outcomes have been discussed in Chapter 11 in greater detail. Commonly used measures of heart therapies might include death, an important outcome, non-fatal myocar- dial infarction, important but less than death and need for revascularization pro- cedure much less important than death. The use of these measures can lead to over-optimistic conclusions regarding the therapy being tested. When combined, multiple or composite outcomes may then show statistical significance. The primary outcome measures were overall number of Survival analysis and studies of prognosis 363 deaths, and of deaths due to stroke, myocardial infarction, or vascular causes. The end result was that there were no decreases in death from stroke or myocardial infarction, but a 20% reduction in deaths in the patients with peripheral arterial disease. If these patient outcomes were considered as separate groups, the differences would not have been statistically significant. Another danger is that some patients may be counted several times because they have several of the outcomes. There are basically three types of data that are used to indicate risk of an out- come. Interval data such as blood pressure is usually considered to be normally distributed and measured on a continuous scale.

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The ingredients in the ideo- logical mix of these communities were a return to nature order atorvastatin 10mg on-line, mysticism order atorvastatin 40mg on line, anarchism discount 10mg atorvastatin otc, vegetarianism and replacing butter with margarine. The communes of hippies in the 1960s shared certain similarities with these early predecessors. As Robert Proctor documents in his book Racial Hygiene: Medi- cine under the Nazis, the early days of Nazi Germany saw 76 the revival of the romantic ideals of health. Paracelsus became the symbol of the new medicine, based on naturopathy, homeopathy, anthro- posophy and other pseudo-sciences. What was needed was a holistic medicine which would restore the German race to its full physical and spiritual potential. The Green movement contains the seeds of a new totalitarianism, but that does not make it Brown. Ambrose Evans-Pritchard, describing how irrational environmentalism has possessed the United States govern- ment, observed that the discredited Marxist ideas of central- ised state control have now found their new expression under 77 an environmental guise in the Green movement. Had he used too much salt at home, even though he appeared to be shunning it in the hospital canteen? Until about the 16th century, death was accepted as a part of the natural order of things. With increasing single- mindedness doctors have seen themselves as valiant generals fighting against their arch-enemy, Death. Deadly treatments were called heroic, doctors were wrenching victims from the clutches of death. Cold steel and searing fire were part of the arma- mentarium of the medical corps in the desperate war against the ultimate aggressor. Yet the dying were more in control of their end than now, when the moment of death may mean the unplugging of a life-support machine. In extreme cases, fear of death may be further compounded by the fear of not being dead when buried. Mon- taigne mused: Having escaped so many precipices of death, whereinto we have seen so many other men fall, we should acknowledge that so extraordinary a fortune as that which hitherto res- cued us from those eminent perils and kept us alive beyond 80 ordinary term of living, is not likely to continue long. Religion may be an immature response to the tragic fate of man, but at least it accepts the harsh reality of human suffering. The healthist manuals have nothing to say about human relationships, loneliness, degra- dation, betrayal, injustice, shattered hopes, despair. Extreme longevity, preferably in a state of permanent youth, was next best and human annals overflow with amusing stories about how this might be achieved. Even in this cen- tury, serious scientists have believed that they have found the means of rejuvenation. While health is not synonymous with a long life, the two concepts are commonly conflated. The pursuit of longevity used to be a private matter, while the health of subjects or slaves was of interest to rulers only in so far as their fitness for military service was concerned. With the rise of nationalism, the same concern applied for the survival of the nation against the enemy. Clearly reasons other than economic ones must be identified to account for the ideology of healthism. In ancient India, great emphasis was put on disease prevention, with specific injunctions about activi- ties such as toothbrushing, combing, diet, exercise, not being a witness or guarantor, avoiding crossroads, or not urinating 2 in the presence of supervisors, cows or against the wind. In ancient Greece, various medical and philosophical sects came up with theories of disease causation and its prevention. Cynics and Stoics viewed disease as an indifferent thing, to be suffered stoically, and if need be, escaped by suicide. Health and beauty were admired and treasured, but seen as a gift of the gods, rather then personal achievement. Out from her box of gifts (the container was, in fact, a large amphora) came wars, pesti- lence, hunger and other scourges of mankind, including old age. In the Lives of Saints, we read about the holy men and women who never washed, and whose bodies were teeming with insects. Disease was a God-sent gift to make the sinner a better man and to remind the faithful of the much worse torments of Hell. Dauphine of Puimichel, who became a saint, was of the opinion that if people knew how useful diseases were for the salvation of 5 the soul, they would queue for them at the market. The adoration of disease by Christians reached a masochistic frenzy in 17th- century convents, when nuns were reported as kissing malod- orous, oozing sores, licking vomit, rubbing themselves with pus from patients, or wrapping their bodies with bandages 6 soaked in the effluvia from chancres. The first widely circulated manual of a healthy lifestyle in Europe was Regimen sanitatis, product of the first medical school in Salerno, some 30 miles south of Naples, which flourished in the 12th and 13th century. It was an eclectic institution, with many women on the staff, and happily mix- ing Greek, Latin, Jewish and Arabic medical learning. The first English translation by Sir John Harington, inventor of the water- closet and a prankster at the Elizabethan court, appeared in 1607. The first lines of the Regimen, loosely translated from the original Latin, read: From the entire school of Salerno, greetings to you, the King of England. If you want to stay hale and healthy, stop worrying about trifles and do not allow anger to take hold of you.

Among the mutations that are believed to be clinically significant quality atorvastatin 20mg, some are thought to confer a higher risk of cancer than others (Gayther et al buy atorvastatin 5mg online. 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 generic atorvastatin 5 mg fast delivery. 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.