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Review of primary care-based physical activity intervention studies: effec- tiveness and implications for practice and future research purchase 250 mg zithromax. Body mass index and mortality: a meta-analysis based on person-level data from twenty-six observational studies order 100 mg zithromax with visa. Effect of body mass index on all-cause mortality and incidence of cardiovascular diseases – report for meta-analysis of prospective studies open optimal cut-off points of body mass index in Chinese adults zithromax 500mg free shipping. Overweight and obesity as determinants of cardiovascular risk: the Framingham experi- ence cheap zithromax 100 mg with visa. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. Joint effects of physical activity, body mass index, waist circumference and waist-to-hip ratio with the risk of cardiovascular disease among middle-aged Finnish men and women. A system- atic review of randomized controlled trials of adding drug therapy, exercise, behaviour therapy or combina- tions of these interventions. Long-term non-pharmacological weight loss interventions for adults with prediabetes. Inﬂuence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure. Effects of weight loss in overweight/obese individuals and long-term hypertension outcomes: a systematic review. Effects of physical inactivity and obesity on morbidity and mortality: current evidence and research issues. Clinical guidelines on the identiﬁcation, evaluation, and treatment of over- weight and obesity in adults – the evidence report. Inﬂuence of sex, age, body mass index, and smoking on alcohol intake and mortality. Alcohol and coronary heart disease reduction among British doctors: confounding or causality? Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. Moderate alcohol use and reduced mortality risk: systematic error in prospective studies. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging ﬁeld of behavioral cardiology. Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychological rehabilitation after myocardial infarction: Multicentre randomised con- trolled trial. Work stress and risk of cardiovascular mortality: prospective cohort study of industrial employees. History of depression, angina, and quality of life after acute coronary syndromes. Social ties and change in social ties in relation to subsequent total and cause-speciﬁc mortality and coronary heart disease incidence in men. Lack of social support and incidence of coronary heart disease in middle-aged Swedish men. Psychological stress and cardiovascular disease: empirical demonstration of bias in a pro- spective observational study of Scottish men. Opportunities for improving the quality of hypertension care in a managed care setting. Blood pressure and long-term coronary heart disease mortality in the Seven Countries study: implications for clinical practice and public health. Effects of an angiotensin- converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6015 individuals with previous stroke or transient ischaemic attack. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. Antihypertensive drugs in very old people: a subgroup meta-analysis of randomised con- trolled trials. Atherosclerosis and left ventricular hypertrophy: persisting problems in treated hypertensive patients. Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. The effect of Irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. Antihypertensive treatment in patients with type–2 diabetes mellitus: what guid- ance from recent controlled randomized trials? Health outcomes associated with various antihypertensive therapies used as ﬁrst-line agents: a network meta-analysis. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly. How strong is the evidence for use of beta-blockers as ﬁrst-line therapy for hypertension? Re-examining the efﬁcacy of beta-blockers for the treatment of hypertension: a meta- analysis. Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Antihypertensive effect of low-dose hydrochlorothiazide alone or in combination with quinapril in black patients with mild to moderate hypertension. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. Renoprotective effect of the angiotensin-receptor antagonist Irbesartan in patients with nephropathy due to type 2 diabetes. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Cost-effectiveness analysis with deﬁned budget: how to distribute resources for the pre- vention of cardiovscular disease? Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. Effect of ﬂuvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.
In ba- bies it may be appropriate to either test for cow’s milk allergy or to perform a therapeutic trial with a cow’s Contact dermatitis milk protein free formula cheap zithromax 100mg without prescription. Deﬁnition r Generalised dry skin (xerosis) requires regular fre- Contact dermatitis is an allergic or irritant-induced der- quent use of emollient moisturisers especially af- matitis arising from direct skin exposure to a substance zithromax 250mg fast delivery. Cream preparations are water based with emulsiﬁers and preservatives and they tend Age todrytheskin buy zithromax 100mg visa. A balance has to be struck between application of sufﬁcient grease and cosmetic satisfaction zithromax 250 mg cheap. Geography The lowest potency that is effective should be used Exposure is most common in the home or industrially and higher potency reserved for resistant cases. Chapter 9: Scaly lesions 387 Aetiology/pathophysiology commonest areas affected are the eyebrows and around r Irritant contact dermatitis (80%) is caused by over- the eyes extending into the scalp. In babies a Oncetheepidermalbarrierisdamagedasecondaryin- widespread lesion of the scalp (cradle cap) is seen, and ﬂammatory response occurs. Psoriasis Deﬁnition Clinical features Psoriasisisachronic,non-infectious,inﬂammatorycon- Contact dermatitis often affects the hands or face. Le- dition of the skin, characterised by well-demarcated ery- sions may also affect the legs of patients with chronic thematous patches and silvery scaly plaques. Management Age The allergens can be identiﬁed by patch testing (see page Peak of onset in teens and early 20s and late onset 55–60 467) and avoided. Seborrhoeic The aetiology is not fully understood but genetic en- dermatitis is a chronic scaly inﬂammatory eruption af- vironmental and immunological components are sug- fecting areas rich in sebaceous glands. There is concor- rum ovale,ayeast that colonises the skin of patients with dance in monozygotic twins and a suggestion of genes seborrhoeic dermatitis; however, it is unclear if this is the located within the major histocompatibility complex cause or effect of the condition. The lesions appear pinkish due to mild erythema and r There is a suggestion of environmental components. The Group A streptococcal sore throat can lead to guttate 388 Chapter 9: Dermatology and soft tissues psoriasis, psoriatic lesions occur at sites of trauma a thin or absent granular layer. Dilated capillaries are and damage (the Koebner phenomenon) and certain¨ seen in the oedematous papillary dermis. Management Psoriasis is a chronic disorder that is managed rather Pathophysiology than cured. Treatments are chosen on the basis of dis- The epidermis is thickened with increased epidermal ease pattern and severity, patient preference and clinical stem cells and keratinocytes. There is a thick silvery scale, which when lifted off char- is a risk of rebound psoriasis on stopping treatment. These treatments are tiple small psoriatic lesions on the trunk often in a expensive and increase the risk of skin cancer. An al- child or young adult with no previous history of pso- ternative may be the use of a high-energy laser that riasis. There is acute onset of diffuse retinoids all of which have systemic toxicity requiring erythema and scaling with sheets of superﬁcial non- monitoring. If the entire skin is affected, it is termed erythrodermic (the von Zumbusch variant). Prognosis This may be associated with systemic upset (malaise, Psoriasis is a lifelong disease with variability in severity fever, diarrhoea) and is potentially life-threatening. Localised forms of pustular psoriasis also occur, such as palmoplantar pustulosis. Pityriases r Flexural or inverse psoriasis affects the inguinal re- gion, axillae and submammary areas. There may not Pityriasis rosea be scales visible due to moisture, the plaques therefore appear erythematous and smooth. Deﬁnition r Nail involvement includes pitting, ridging and ony- Pityron is Greek word for bran. Nail involvement is speciﬁcally associated diseases characterised by ﬁne, bran-like scales. Aetiology Microscopy The cause is unknown, human herpes virus 7 has been There is inﬁltration of the strium corneum with neu- suggested; however, the virus is not always detectable in trophils, epidermal hyperplasia with hyperkeratosis and patients with pityriasis rosea. Chapter 9: Erythematous lesions 389 Clinical features Clinical features Most cases commence with a herald patch, a single Lesions are superﬁcial hypopigmented macules appear- salmonpinklesion2–5cmindiameterwithcentralclear- ing light brown or salmon coloured with a ﬁne scale. Days later crops of similar They are most seen commonly on the upper trunk and smaller oval plaques appear and proximal extremities. The lesions distribute along dermatomal lines, which is most evident on the back appearing in a ‘Christmas tree’ Management pattern. Recurrence is common, and frequent relapses may require prophy- Management laxis with topical selenium sulﬁde or an oral conazole. Steroids and phototherapy may be of value for associated The loss of colour in the skin may persist for several itching. Deﬁnition Theichthyosesaredisordersofkeratinisation,whichmay Pityriasis versicolor be congenital or acquired characterised by a generalised scaling of the skin due to hyperkeratosis (see Table 9. Deﬁnition Pityriasis (bran-like) versicolour (varying in colour) is Management achronic infection characterised by multiple macular Topical emollients and bath additives are used to help patches varying in size and degree of brown pigmenta- avoid the dryness. Aetiology Caused by infection by the commensal yeast Pityrospo- Erythematous lesions rumorbiculare (also known as Malessezia furfur, Pity- rosporum ovale and Malassezia ovalis). Infection results Erythema multiforme from conversion of the yeast to the mycelial or hyphal form, which may be triggered by heat and humidity and Deﬁnition immunosuppression. Theyeastreleasescarboxylicacids, Aself-limiting hypersensitivity reaction affecting the which inhibit melanin production. Lamellar ichthyosis Autosomal recessive 1 in 60,000, may at birth cause the collodion baby with red scaly skin and ectropion, may resolve or progress to other forms Acquired ichthyosis Non-inherited Associated with inﬂammatory disorders, endocrine anomalies, and neoplasia especially Hodgkin’s disease 390 Chapter 9: Dermatology and soft tissues Aetiology Sex 50% of cases have no obvious underlying cause. Aetio- F > M logical agents include: r Herpes simplex in 33% of cases; may cause recurrent Aetiology attacks. Clinical features r Gastrointestinal disorders: Inﬂammatory bowel dis- Lesions are pinkish red erythematous papules/plaques ease, Behc¸et’sˆ syndrome and bacterial gastroenteri- with central clearing or concentric rings (target lesions). Disseminated rash with mucosal Clinical features involvement with conjunctivitis and necrotic mucosal Painfulbluish-rednodulesupto5cmindiameterappear ulcers is termed Stevens–Johnson syndrome. This is of- in crops over 2 weeks on the anterior surface of both ten associated with systemic symptoms. The withdrawal of any causative drug and treatment of any associated infection is essential. Short courses of Management oral steroids are sometimes used but their efﬁcacy and Symptomatic treatment and management of any under- safetyareunclear. Recovery may take weeks, and tiforme resulting from herpes simplex can be prevented there may be recurrence. Urticaria Prognosis Disease is usually self-limiting clearing in 2–3 weeks but Deﬁnition death can occur with Stevens–Johnson syndrome. Urticaria is an itchy erythematous eruption ranging from nettle rash to large weals/plaques with palpable skin oedema. Most cases of urticaria are acute and self- Erythema nodosum limiting within a few hours, occasionally with recurrent episodes for up to 6 weeks. Chronic urticaria lasts from 6 weeks Erythema nodosum is an immune-mediated disorder and up to 10 years. There is often no identiﬁable trigger resulting in red tender pretibial subcutaneous nodules. Any trigger factor should be identiﬁed and avoided IgE mediated Food allergy (egg, milk, wherever possible. Medical treatment is used for symp- peanut) Drug reaction (penicillin, tomrelief in acute urticaria and chronic urticaria where cephalosporin) triggers are not identiﬁable. Insect stings (bees, wasps) 1 Antihistamines Contact allergy (latex) r H receptor blockers such as loratadine are the 1 Complement mediated Hereditary angio-oedema mainstay of treatment. Serum sickness r H receptor blockers such as ranitidine may be use- Transfusion reactions 2 Direct mast cell Opiates (morphine, codeine) ful in conjunction with an H1 blocker in refractory degranulation Neuromuscular blocking cases. Prolonged courses in Vancomycin Radiological contrast agents chronic urticaria are associated with signiﬁcant side Infections Coxsackie A and B effects and adrenal suppression. Uncommon in very Rarely urticaria may bepart of a systemic disease, such as young and very old. Sex M = F Pathophysiology Aetiology/pathophysiology Urticaria results from the degranulation of cutaneous The exact cause is unknown but it is thought that there mast cells causing dilation of local capillaries and leakage is a T cell autoimmune reaction to keratinocytes.
Ordinal data are nominal data for which the order of the variables has impor- tance and intrinsic meaning discount zithromax 250 mg on line. Typical examples of ordinal data include certain pain scores that are measured by scales called Likert scales zithromax 250mg overnight delivery, severity of injury scores as reﬂected in a score such as the Trauma Score where lower numbers are pre- dictive of worse survival than higher ones buy discount zithromax 250mg online, or the grading and staging of a tumor where higher number stages are worse than lower ones zithromax 500 mg lowest price. Common questionnaires asking the participant to state whether they agree, are neutral, or disagree with a statement are also examples of an ordinal scale. Although there is a directional value to each of these answers, there is no numerical or mathematical relation- ship between them. Interval data are ordinal data for which the interval between each number is also a meaningful real number. However, interval data have only an arbitrary zero point and, therefore, there is no proportionality ratio relationship between two points. One example is temperature in degrees Celsius where 64◦Cis32 C hotter◦ than 32◦C but not twice as hot. This makes the results take on meaning for both absolute and relative changes in the vari- able. Examples of ratio variables are the temperature in degrees Kelvin where 100◦ Kelvin is 50◦K hotter than 50◦K and is twice as hot, age where a 10-year- old is twice as old as a 5-year-old, and common biological measurements such Instruments and measurements: precision and validity 69 as pulse, blood pressure, respiratory rate, blood chemistry measurements, and weight. This is called the number of signiﬁcant places, which is taught in high school and college, although it is often forgotten by students quickly thereafter. Height is an example of a continuous measure since a person can be 172 cm or 173 cm or 172. For exam- ple, a piano is an instrument with only discrete values in that there are only 88 keys, therefore, only 88 possible notes. Scoring systems like the Glasgow Coma Score for measuring neurological deﬁcits, the Likert scales mentioned above, and other ordinal scales contain only discrete variables and mathematically can have only integer values. We commonly use dichotomous data to describe binomial outcomes, which are those variables that can have only two possible values. Obvious examples are alive or dead, yes or no, normal or abnormal, and better or worse. This has the effect of dichotomizing the value of the serum sodium into either hypernatremic or not hypernatremic. Measurement in clinical research All natural phenomena can be measured, but it is important to realize that errors may occur in the process. Random error leads to a lack of precision due to the innate variability of the biological or sociological system being studied. For example, in a given popula- tion, there will be a more or less random variation in the pulse or blood pres- sure. Many of these random events can be described by the normal distribution, which we will discuss in Chapter 9. An imprecise instrument will get slightly different results each time the same event is measured. For example, serum sodium measured inside rat muscle cells will show less random error than the degree of depression in humans. There can also be innate variability in the way that 70 Essential Evidence-Based Medicine different researchers or practicing physicians interpret various data on certain patients. Systematic error represents a consistent distortion in direction or magni- tude of the results. Systematic or systemic error is a function of the person making the measurement or the calibration of the instrument. For example, researchers could consistently measure blood pressure using a blood-pressure cuff that always reads high by 10 mmHg. More commonly, a measurement can be inﬂuenced by knowledge of other aspects of the patient’s situation lead- ing to researchers responding differently to some patients in the study. Another source of systematic error can occur when there is non- random assignment of subjects to one group in a study. For instance, researchers could preferentially assign patients with bronchitis to the placebo group when studying the effect of antibiotics on bronchitis and pneumonia. This would be problematic since bronchitis almost always gets better on its own and pneu- monia sometimes gets better on its own, but it is less likely and occurs more slowly. Then, if the patients assigned to placebo get better as often as those tak- ing antibiotics, the cause of the improvement is uncertain since it may have occurred because the placebo patients were going to get better more quickly anyway. The researcher’s job is to minimize the error in the study to minimize the bias in the study. Researchers are usually more successful at reducing systematic error than random error. Overall, it is the reader’s job to determine if bias exists, and if so to what extent and in what direction that bias is likely to change the study results. Instruments and how they are chosen Common instruments include objective instruments like the thermometer or sphygmomanometer (blood-pressure cuff and manometer) and subjective instruments such as questionnaires or pain scales. By their nature, objective measurements made by physical instruments such as automated blood-cell counters tend to be very precise. However, these instruments may also be affected by random variation of biological systems in the body. An example of this is hemodynamic pressure measurements such as arterial or venous pres- sure, oxygen saturation, and airway pressures taken by transducers. The actual measurement may be very precise, but there can be lots of random variation around the true measurement result. Subjective instruments include questions that must be answered either yes or no or with an ordinal scale (0, 1, 2, 3, 4, or 5) or by placing an x on a pre-measured line. Measures of pain or anxiety are Instruments and measurements: precision and validity 71 common examples and these are commonly known to be unreliable, inaccurate, and often imprecise. Overall, measurements, the data that instruments give us, are the ﬁnal goals of research. They are the result of applying an instrument to the process of sys- tematically collecting data. Common instruments used in medicine measure the temperature, blood pressure, number of yes or no answers, or level of pain. The quality of the measurements is only as good as the quality of the instrument used to make them. The researcher must select instruments that will measure the phenomena of inter- est. If the researcher wishes to measure blood pressure accurately and precisely, a standard blood-pressure cuff would be a reasonable tool. The researcher could also measure blood pressure using an intra-arterial catheter attached to a pres- sure transducer. This will give a more precise result, but the additional precision may not help in the ultimate care of the patient. If survival is the desired out- come, a simple record of the presence or absence of death is the best measure. For measuring the cause of death, the death certiﬁcate can also be the instru- ment of choice but has been shown to be inaccurate. When subjective outcomes like pain, anxiety, quality of life, or patient satis- faction are measured, the selection of an instrument becomes more difﬁcult. Some patients will react more strongly and show more emotion than others in response to the same levels of pain. There are standardized pain scores available that have been validated in research trials. A 10-cm line is placed on the paper with one end labeled “no pain at all,” and the other end “worst pain ever. If this exercise is repeated and the patient reports the same level of pain, then the scale is validated. The best outcome measure when using this scale becomes the change in the pain score and not the absolute score. Since pain is quantiﬁed differently in differ- ent patients, it is only the difference in scores that is likely to be similar between patients. In fact, when this was studied, it was found that patients would use con- sistently similar differences for the same degree of pain difference. Another type of pain score is the Likert Scale, which is a ﬁve- or six-point ordi- nal scale in which each of the points represents a different level of pain. A sample Likert Scale begins with 0 = no pain, continues with 1 = minimal pain, and ends 1 K.
Blinding prevents observer bias discount zithromax 100mg on line, contamination generic zithromax 100 mg otc, and cointervention bias in either group trusted 500mg zithromax. No matter how honest generic 250 mg zithromax, researchers may subconsciously tend to ﬁnd what they want to ﬁnd. The simplist test is to ask participants if they knew which therapy they were getting. If there is no difference in the responses between the two groups, the blinding was successful and there is not likely to be any bias in the results due to lack of blinding. Studies of different surgical methods or operations can be done with blinding by using sham operations. This has been successfully performed and in some cases found that standard therapeutic surgical procedures were not particularly ben- eﬁcial. A recent series of studies showed that when compared to sham arthro- scopic surgery for osteoarthritis, actual arthroscopic surgery had no beneﬁt on outcomes such as pain and disability. Similar use of sham with acupuncture showed an equal degree of beneﬁt from real acupuncture and sham acupunc- ture, with both giving better results than patients treated with no acupuncture. A recent review of studies of acupuncture for low back pain found that there was a dramatic effect of blinding on the outcomes of the studies. However, when blinded studies were ana- lyzed, no such effect was found and the results, presented in Table 15. The intervention must be well described, including dose, frequency, route, precautions, and monitoring. The interven- tion also must be reasonable in terms of current practice since if the inter- vention being tested is being compared to a non-standard therapy, the results will not be generalizable. The availability, practicality, cost, invasiveness, and ease of use of the intervention will also determine the generalizability of the study. In addition, if the intervention requires special monitoring it may be too expensive and difﬁcult to carry out and therefore, impractical in most ordinary situations. Instruments and measurements should be evaluated using the techniques dis- cussed in Chapter 7. Appropriate outcome measures should be clearly stated, and their measurements should be reproducible and free of bias. Subjective outcomes don’t automatically invalidate the study and observer blinding can minimize bias from subjective outcomes. Measurements should be made in a manner that ensures consistency and maximizes objectivity in the way the results are recorded. For statistical reasons, beware of composite outcomes, subgroup analysis, and post- hoc cutoff points, which can all lead to Type I errors. The study should be clear about the method, frequency, and duration of patient follow-up. This is important because patients may leave the study for important reasons such as death, treatment complications, treatment ineffec- tiveness, or compliance issues, all of which will have implications on the appli- cation of the study to a physician’s patient population. A study attrition rate of > 20% is a rough guide to the number that may invalidate the ﬁnal results. How- ever, even a smaller percentage of patient drop-outs may affect the results of a study if not taken into consideration. The results should be analyzed with an intention-to-treat analysis or using a best case/worst case analysis. In this method, all patient outcomes are counted with the group to which the patient was originally assigned even if the patient dropped out or switched groups. This approximates real life where some patients drop out or are non-compliant for various reasons. Patients who dropped out or switched therapies must still be accounted for at the end of the trial since if their fates are unknown, it is impos- sible to accurately determine their outcomes. Some studies will attempt to use statistical models to estimate the outcomes that those patients should have had if they had completed the study, but the accuracy of this depends on the ability of the model to mimic reality. A good example of intention-to-treat analysis was in a study of survival after treatment with surgery or radiation for prostate cancer. The group randomized to radical prostatectomy surgery or complete removal of the prostate gland, did much better than the group randomized to either radiation therapy or watchful waiting with no treatment. Some patients who were initially randomized to the surgery arm of the trial were switched to the radiation or watchful waiting arm of the trial when, during the surgery, it was discovered that they had advanced and inoperable disease. These patients should have been kept in their original surgery group even though their cancerous prostates were not removed. When the study was re-analyzed using an intention-to-treat analysis, the survival in all three groups was identical. Removing those patients biased the original study results since patients with similarly advanced cancer spread were not removed from the other two groups. Remov- ing patients after randomization for reasons associated with the outcome is patently biased and grounds to invalidate the study. Leaving them in the analysis as an intention-to-treat is honest and will not inﬂate the results. However, if the outcomes of patients who left the study are not known, a best case/worst case scenario should be applied and clearly described so that the reader can deter- mine the range of effects applicable to the therapy. In the best case/worst case analysis, the results are re-analyzed considering that all patients who dropped out or crossed over had the best outcome possible or worst outcome possible. This should be done by adding the drop-outs of the intervention group to the successful patients in the intervention group and at the same time subtracting the drop-outs of the comparison group from the success- ful patients in that group. The opposite process, subtracting drop out patients from the intervention group and adding them to the comparison group, should then be done. If this range is very large, we say that the results are sensitive to small changes that Randomized clinical trials 173 could result from drop-outs or crossovers. If the range is very small, we call the results robust, as they are not likely to change drastically because of drop-outs or crossovers. Lack of compliance may inﬂuence outcomes since the reason for non-compliance may be directly related to the intervention. Other clinically important outcomes that should be measured include adverse effects, direct and indirect costs, invasiveness, and monitoring of an intervention. A blinded and independent observer should measure these outcomes, since if the outcome is not objectively measured, it may limit the usefulness of the therapy. Remember, no adverse effects among n patients could signify as many as 3/n adverse events in actual practice. Results should be interpreted using the techniques discussed in the sections on statistical signiﬁcance (Chapters 9–12). Discussion and conclusions The discussion and conclusions should be based upon the study data and lim- ited to settings and subjects with characteristics similar to the study setting and subjects. Good studies will also list weaknesses of the current research and offer directions for future research in the discussion section. Also, the author should compare the current study to other studies done on the same intervention or with the same disease. In summary, no study is perfect, all studies have ﬂaws, but not all ﬂaws are fatal. After evaluating a study using the standardized format presented in this chapter, the reader must decide if the merits of a study outweigh the ﬂaws before accepting the conclusions as valid. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. An example of this phenomenon can be seen in the systematic review of studies of acupuncture for back pain that was described earlier. L’Abbep´ lotsare a graphic technique for presenting the results of many indi- vidual clinical trials. It is a way of looking for the presence of bias in the studies done on a single question. The plot shows the propor- tion of patients in each study who improved taking the control therapy against the proportion who improved taking the active treatment. Each study is repre- sented by one point and the size of the circle around that point is proportional to the sample size of the study.