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Remov- ing patients after randomization for reasons associated with the outcome is patently biased and grounds to invalidate the study discount 100 mg januvia with visa diabete 97. Leaving them in the analysis as an intention-to-treat is honest and will not inflate the results order 100mg januvia visa diabetes type 1 zelftest. 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. The studies closest to the diagonal show the least effect of therapy, and farther from the diagonal show a greater effect. In addi- tion to getting an idea of the strength of the difference between the two groups, one can also look for the effects of blinding, sample size, or any other factor on the study results. One can clearly see that the results of the blinded trials were less spectacular than the unblinded ones. It is a useful technique to determine optimal therapy in a single patient when there appears to be no signif- icant advantage of one therapy over another based on reported clinical trials. In order to justify the trial, the effectiveness of therapy must really be in doubt, the treatment should be continued long-term if it is effective, and the patient must be highly motivated to allow the researcher to do an experiment on them. It is helpful if there is a rapid onset of action of the treatment in question and rapid cessation when treatment is discontinued. There should be easily measurable and clinically relevant outcome measures and sensible criteria for stopping the trial. Additionally, the patient should give informed consent before beginning the trial. The researcher must have a willing pharmacist and pharmacy that can dis- pense identical, unlabeled active and placebo or comparison medications. Also, the patient should be asked if they knew which of the two treatments they were taking and a statistician should be available to help evaluate the results. Ethical issues Finally, there are always ethical issues that must be considered in the evalua- tion of any study. This is a problem in some resuscitation studies, where other forms of consent such as substituted or implied consent may be used. Decisions about whether or not to use the results of unethical studies are very difficult and beyond the scope of this book. As always, in the end, readers must make their own ethical judgment about the research. All the major medical journals now require authors to list potential conflicts of interest with their submissions. These are important to let the reader know that there may be a greater potential for bias in these studies. However, there are always potential reasons to suspect bias based upon other issues that may not be so apparent. These include the author’s need to “publish or perish,” desire to gain fame, and belief in the correctness of a particular hypothesis. A recent study on the use of bone-marrow transplantation in the treatment of stage 3 breast cancers showed a positive effect of this therapy. However, some time after publi- cation, it was discovered that the author had fabricated some of his results, mak- ing the therapy look better than it actually was. The site gives information about the purpose of the clinical trial, who may participate, locations, and phone numbers for more details. The purpose of the registry is to get the details of the trial published on-line prior to initiation of the trial itself. This way, the researchers cannot spin the results to look better by reporting different outcomes than were originally specified or by using different methods than originally planned. Most journals will no longer publish trials that are not registered in this or a similar international registry. The question of placebo controls is one ethical issue which is constantly being discussed. Since there are therapies for almost all diseases, is it ever ethical to have a placebo control group? This occurs when the clinician is unsure about the suitability of a therapy and there is no other therapy that works reasonably well to treat the condition.

Typical early symptoms of Alzheimer’s may include: Memory Disorientation Regularly forgetting recent Disorientation buy cheap januvia diabetic leg rash, especially events cheap januvia 100 mg with mastercard diabetes mellitus scholarly articles, names and faces. Mood and behaviour Misplacing things Some people become Regularly misplacing disinterested in what’s items or putting them in happening around them, odd places. As Alzheimer’s progresses: Memory and thinking skills People will fnd that their ability to remember, think and make decisions worsens. Behaviour A person’s behaviour may change and some people can become sad or depressed. Anger and agitation become more common and people may develop anxieties or phobias. Hallucinations People may experience hallucinations, where they may see things or people that aren’t there. Unsteadiness People may become increasingly unsteady on their feet and fall more often. Daily activities People gradually require more help with daily activities like dressing, toileting and eating. These are likely to include: • Asking you some questions about your symptoms and medical history. Sometimes, if symptoms are mild, looking for change with time is the best way to be sure if anything is wrong. You may also be asked to undergo other tests, including brain scans and blood tests. Together all of these things will help a doctor fnd out about any problems in memory or thinking and the likely cause. If you are assessed for the possibility of having Alzheimer’s or another form of dementia, you can choose not to know the diagnosis. If you are given a diagnosis of Alzheimer’s, you may be offered various types of support. You may also be prescribed drugs or other treatments to help with symptoms or improve your quality of life. Non-drug treatments Cognitive stimulation activities are designed to stimulate thinking skills and engage people who have Alzheimer’s. The benefts of cognitive stimulation for people with Alzheimer’s could include improvement in memory, thinking skills and quality of life. People with mild to moderate dementia, including Alzheimer’s, should be given the opportunity to participate in cognitive stimulation programmes, if available. These drugs work by increasing the amount of a chemical called acetylcholine which helps messages to travel around the brain. Cholinesterase inhibitors do not prevent the disease from progressing, but may help people to function at a slightly higher level than they would do without the drug. Some people with Alzheimer’s fnd that their condition improves by taking a cholinesterase inhibitor. This may include improvement in thinking, memory, communication or day-to-day activities. The most common are feeling sick, vomiting, diarrhoea, being unable to sleep, muscle cramp and tiredness. Memantine does not stop the disease from progressing but can help with some symptoms. Others may fnd that their condition stays the same, when they would have expected it to decline. The most common side effects are headaches, dizziness, drowsiness and constipation. People with more severe symptoms may also be offered an antidepressant drug, although these are not always suitable for someone with Alzheimer’s. This is likely to depend on your preference as well as the availability of treatments. In some circumstances antipsychotic drugs such as risperidone (Risperdal) may be used to relieve very severe symptoms. These drugs are not suitable for everyone and your doctor will carefully consider what is appropriate. These drugs can have serious side effects and their use should be carefully monitored. For more information on treatments for Alzheimer’s, please ask for our separate booklet ‘Treatments for dementia’. Accessing services and support can make a positive difference to someone with dementia and their family. Many organisations provide information, support and care services to people affected by dementia, as well as families and carers. For more information, request our booklet ‘Caring for someone with dementia: organisations that can help’, or visit our website at www. Among the most prominent are the build-up of two proteins, called amyloid and tau. Research suggests that both of these are involved in the disease process, but the exact sequence of events is still not understood. We still need to learn more about why these proteins build up in the brain and how they damage nerve cells. Research is underway to understand more about what happens in the brain during Alzheimer’s. Someone’s risk of developing Alzheimer’s is made up of a number of different elements. The biggest risk factor for developing late-onset Alzheimer’s is age – the older you are the more likely you are to develop it. While we can’t change our age or our genes, research is underway to learn more about ways we might help prevent Alzheimer’s or lower our risk. Lifestyle Some of the risk factors for Alzheimer’s are the same as for cardiovascular disease (like heart disease and stroke). By leading a healthy lifestyle and taking regular exercise you will be helping to keep your heart healthy. To keep healthy: be active and exercise regularly keep cholesterol at a healthy level don’t smoke maintain a healthy weight eat a healthy balanced diet only drink alcohol within recommended limits. Some research has suggested that if you have a parent or grandparent with Alzheimer’s and they developed Alzheimer’s over the age of 65, then your risk of developing Alzheimer’s may be slightly higher than someone with no family history. Research has identifed some genes that may be associated with a higher risk of late-onset Alzheimer’s in some people. In these cases, many members of the same side of the family are affected, often in their 30s, 40s or 50s.

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We will talk about applying these numbers in a real clinical situation in a later chapter purchase 100mg januvia mastercard diabetes symptoms of high sugar. It is always necessary to be aware of biases in a study order genuine januvia line diabetes type 1 care plan, and this example is no different. It was done on 156 children who presented to an emergency department with severe diarrhea and were entered into the study. This meant that someone, either the resident or attending physician on duty at the time, thought that the child had infectious 260 Essential Evidence-Based Medicine or bacterial diarrhea. Therefore, they were already screened before any testing was done on them and the study is subject to filter or selection bias. This simply means that the population in the study may not be representative of the pop- ulation of all children with diarrhea like the ones being seen in a pediatric or family-practice office. The next chapter will deal with this problem and how to generalize the results of this study to real patients. Albert Einstein (1879–1955) Learning objectives In this chapter you will learn: r how to define predictive values of positive and negative test results and how they differ from sensitivity and specificity r the difference between odds and probability and how to use each correctly r Bayes’ theorem and the use of likelihood ratios to modify the probability of a disease r how to define, calculate, and use interval likelihood ratios for a diagnostic test r how to calculate and use positive and negative predictive values r how to use predictive values to choose the appropriate test for a given diag- nostic dilemma r how to apply basic test characteristics to solve a clinical diagnostic problem r the use of interval likelihood ratios in clinical decision making In this chapter, we will be talking about the application of likelihood ratios, sen- sitivity, and specificity to a patient. Introduction Likelihood ratios, sensitivity, and specificity of a test are derived from studies of patients with and without disease. They are stable and essential characteristics of the test that give us the probabilities of a positive or negative test if the patient 261 262 Essential Evidence-Based Medicine does or does not have disease. This is not the information a clinician needs to know in order to apply the test to a single patient. What the clinician needs to know is: if a patient has a positive test, what is the likelihood that patient has the disease? For a given patient, how will the probability of dis- ease change given a positive or negative test result? Applying likelihood ratios or sensitivity and specificity to a selected pretest probability of disease will give the post-test probability to answer this question. The first uses Bayes’ theorem, while the second calculates the predictive values of a positive and negative test directly from sensitivity, speci- ficity, and prevalence using the 2 × 2 table. If the test comes back positive, it shows the probability that this patient really has the disease. Probabilistically, it is expressed as P[D+|T +], the probability of disease if a positive test occurs. That is the proportion of people with a positive test who do not have disease and will then be falsely alarmed by a positive test result. If the test comes back negative, it shows the probability that this patient really does not have the disease. Prob- abilistically, it is expressed as P[D– | T –], the probability of not having disease if a negative test occurs. That is the proportion of people with a negative test who have disease and will be falsely reassured by a negative test result. In eighteenth-century English, it said: “The probability of an event is the ratio between the value at which an expec- tation depending on the happening of the event ought to be computed and the value of the thing expected upon its happening. In simple language, the theorem was an updated way to predict the odds of an event happening when confronted with new information. In making diagnoses Bayes’ theorem and predictive values 263 in clinical medicine, this new information is the likelihood ratio. Bayes’ theorem was put into mathematical form by Laplace, the discoverer of his famous law. Its use in statistics was supplanted at the start of the twentieth century by Sir Ronald Fisher’s ideas of statistical significance, the use of P < 0. We won’t get into the actual formula in its usual and original form here because it only involves another very long and useless formula. A derivation and the full mathematical formula for Bayes’ theorem are given in Appendix 5, if interested. Odds describe the chance that something will happen against the chance it will not happen. Probability describes the chance that something will happen against the chance that it will or will not happen. The odds of an outcome are the number of people affected divided by the number of people not affected. In contrast, the probability of an outcome is the number of people affected divided by the number of people at risk or those affected plus those not affected. Probability is what we are estimat- ing when we select a pretest probability of disease for our patient. Let’s use a simple example to show the relationship between odds and proba- bility. If we have 5 white blocks and 5 black blocks in a jar, we can calculate the probability or odds of picking a black block at random and of course, without looking. For every one black block that is picked, on average, one white block will be picked. In horse racing or other games of chance, the odds are usually given backward by convention. This means that this horse is likely to lose 7 times for every eight races he enters. Here we answer the ques- tion of how many times will he have to race in order to win once? The probability of him winning any 264 Essential Evidence-Based Medicine Black and white blocks in a jar Odds Probability 9/1 = 9 9/10 = 0. Probability = Odds/(1 + Odds) To convert probability to odds: Odds = Probability/(1− Probability) one race is 1 in 8 or 1/8 or 0. If he were a better horse and the odds of him winning were 1 : 1, or one win for every loss, the odds could be expressed as 1/1 or 1. Odds are expressed as one number to another: for example, odds of 1 : 2 are expressed as “one to two” and equal the fraction 0. These two expressions and numbers are the same way of saying that for every three attempts, there will be one successful outcome. There are mathematical formulas for converting odds to probability and vice versa. This says post-test odds of Bayes’ theorem and predictive values 265 Fig. We get the pretest probability of disease from our differential diagnosis list and our estimate of the possibility of disease in our patient. The pretest probability is converted to pretest odds and multiplied by the likelihood ratio. This results in the post-test odds, which are converted back to a probability, the post-test probability.

The average molecular weight of resistant maltodextrins is 2 best 100 mg januvia diabetes definition and causes,000 daltons and consists of polymers of glucose containing α-(1-4) and α-(1-6) glucosidic bonds buy januvia 100mg with mastercard metabolic disease panel, as well as 1-2 and 1-3 linkages. Resistant dextrins can potentially be classified as Functional Fibers when sufficient data on physiological benefits in humans are documented. Resistant starch is naturally occurring, but can also be produced by the modification of starch during the processing of foods. Resistant starch is estimated to be approximately 10 percent (2 to 20 percent) of the amount of starch consumed in the Western diet (Stephen et al. Along the gastrointestinal tract, properties of fiber result in differ- ent physiological effects. Effect on Gastric Emptying and Satiety Consumption of viscous fibers delays gastric emptying (Low, 1990; Roberfroid, 1993) and expands the effective unstirred layer, thus slowing the process of absorption once in the small intestine (Blackburn et al. A slower emptying rate means delayed digestion and absorp- tion of nutrients (Jenkins et al. For example, Stevens and coworkers (1987) showed an 11 percent reduction in energy intake with psyllium gum intake. Postprandial glucose concentration in the blood is thus lower after the consumption of viscous fiber than after consumption of digestible carbohydrate alone (Benini et al. The extended presence of nutrients in the upper small intestine may promote satiety (Sepple and Read, 1989). Fermentation Fibers may be fermented by the colonic microflora to carbon dioxide, methane, hydrogen, and short-chain fatty acids (primarily acetate, propi- onate, and butyrate). Foods rich in hemicelluloses and pectins, such as fruits and vegetables, contain Dietary Fiber that is more completely ferment- able than foods rich in celluloses, such as cereals (Cummings, 1984; Cummings and Englyst, 1987; McBurney and Thompson, 1990). There appears to be no relationship between the level of Dietary Fiber intake and fermentability up to very high levels (Livesey, 1990). Butyrate, a four-carbon, short-chain fatty acid, is the preferred energy source for colon cells (Roediger, 1982), and lack of butyrate production, absorption, or metabo- lism is thought by some to contribute to ulcerative colitis (Roediger, 1980; Roediger et al. Others have suggested that butyrate may be protec- tive against colon cancer (see “Dietary Fiber and the Prevention of Colon Cancer”). However, the relationship between butyrate and colon cancer is controversial and the subject of ongoing investigation (Lupton, 1995). Once absorbed into the colon cells, butyrate can be used as an energy source by colonocytes (Roediger, 1982); acetate and propionate travel through the portal vein to the liver, where propionate is then utilized by the liver. A small proportion of energy from fermented fiber is used for bacterial growth and mainte- nance, and bacteria are excreted in feces, which also contain short-chain fatty acids (Cummings and Branch, 1986). Differences in food composi- tion, patterns of food consumption, the administered dose of fiber, the metabolic status of the individual (e. Because the process of fermentation is anaerobic, less energy is recovered from fiber than the 4 kcal/g that is recovered from carbohy- drate. While it is still unclear as to the energy yield of fibers in humans, current data indicate that the yield is in the range of 1. Physiological Effects of Isolated and Synthetic Fibers This section summarizes the fibers for which there is a sufficient data- base that documents their beneficial physiological human effects, which is the rationale for categorizing them as Functional Fibers. It is important to note that discussions on the potential benefits of what might eventually be classified as Functional Fibers should not be construed as endorsements of those fibers. While plant-based foods are a good source of Dietary Fiber, isolated or synthetic fibers have been developed for their use as food ingredients and because of their beneficial role in human health. In 1988 Health Canada published guidelines for what they considered to be “novel fiber sources” and food products containing them that could be labeled as a source of fiber in addition to those included in their 1985 definition (Health Canada, 1988). The rationale for these guidelines was that there were safety issues unique to novel sources of fiber, and if a product was represented as containing fiber, it should have the beneficial physiological effects associated with dietary fiber that the public expects. The guidelines indicated that both safety and efficacy of the fiber source had to be estab- lished in order for the product to be identified as a source of dietary fiber in Canada, and this had to be done through experiments using humans. Detailed guidelines were later produced for the clinical studies required to assess laxation effects, as this was the physiological function most often used by industry when seeking approval for a novel fiber source (Health Canada, 1997). For each of the fiber sources discussed below, studies will be summarized that relate to one of the three measures of efficacy identified by Health Canada, as these are the three most commonly accepted beneficial effects of fibers. A more complete discussion of these three measures of efficacy may be found later in this chapter. In addition, other potentially efficacious effects will be noted where studies are available. As interest has increased in fiber, manufacturers have isolated various types of fiber from a wide range of carbohydrate sources added to foods. Many of these isolated materials are used as food additives based on func- tional properties such as thickening or fat reduction. As enzymatic and other technologies evolve, many types of polysaccharides will continue to be designed and manufactured using plant and animal synthetic enzymes. Examples in this category include modified cellulose, in which the hydroxyl groups on the glucose residues have been substituted to varying degrees with alkyl groups such as methyl and propyl; fructooligosaccharides manu- factured from sucrose; and polydextrose synthesized from glucose. In some instances, fibers isolated from plants or manufactured chemically or synthetically have demonstrated more powerful beneficial physiological effects than a food source of the fiber polysaccharide. From a meta-analysis of about 100 studies of changes in stool weight with various fiber sources, investigators have calculated the increase in fecal weight due to fiber ingestion (Cummings, 1993). As noted later in this chapter, an increase in fecal weight does not necessarily equate with enhanced laxation, so this needs to be considered in interpreting the results of fecal bulking studies. In a randomized, crossover study designed to compare the effects of supplemental pectin (12 g/d), cellulose (15 g/d), and lignin (12 g/d) on stool characteristics of healthy volunteers, cellulose was the only fiber that significantly decreased (–27 percent) mean stool transit time and increased mean wet stool weight (+57 percent) (Hillman et al. Cellulose is often used as the placebo in studies designed to test the efficacy of fibers on decreasing serum cholesterol concentrations. Cellulose is either neutral with respect to blood cholesterol concentrations (Hillman et al. Similar to the relationship between cellulose and serum cholesterol concentrations, cellulose is also often used as a placebo in studies that evaluate the effect of fiber on blood glucose and insulin concentrations. Cellulose is ineffective in decreasing the postprandial glucose response (Librenti et al. There are a number of animal studies that have suggested that chitin and chitosan may decrease lipid absorption and thus the amount of fat entering the blood (Gallaher et al. Therefore, blood cholesterol and triacylglycerol concentrations have been shown to be reduced with chitosan intake in animals (Chiang et al. These results, however, have not always been observed in controlled intervention trials with humans. More intervention studies are needed to further understand the role of chitin and chitosan in the attenuation of blood lipid concentration in humans. There are no known reports in humans on chitin or chitosan intake and the attenuation of blood glucose responses. Because chitosan has been shown in some animal studies to reduce fat absorption, it has been proposed that chitosan intake can aid in weight reduction. Significantly reduced body weights were observed when chickens were fed 30 g/kg of chitosan (Razdan et al.

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