睿学教育Wisdome Education

John Lynn Jefferies, MD, MPH

• Assistant Professor
• Adult and Pediatric Cardiology
• Baylor College of Medicine
• Divisions of Adult Cardiovascular Diseases
• and Pediatric Cardiology
• Texas Children? Hospital
• Texas Heart Institute at St. Luke? Episcopal Hospital
• Houston, Texas

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Breeding rats on amino acid imbalanced diets for three consecutive generations affects the concentrations of putative amino acid transmitters in the developing brain blood pressure 200 over 100 buy toprol xl with amex. Obligatory nitrogen losses and factorial calculations of protein requirements of pre-school children blood pressure medication hydroxyzine buy toprol xl american express. Human protein requirements: Nitrogen balance response to graded levels of egg protein in elderly men and women blood pressure chart british heart foundation buy toprol xl 50 mg. Obligatory urinary and faecal nitrogen losses in young Chilean men fed two levels of dietary energy intake. The pattern of intestinal substrate oxidation is altered by protein restriction in pigs. New equations for estimating body fat mass in pregnancy from body density or total body water. Qualitative analysis of human milk produced by women consuming a maize-predominant diet typical of rural Mexico. Integumental nitrogen losses of pre-school children with different levels and sources of dietary protein intake. Muscle amino acid metabolism at rest and during exercise: Role in human physiology and metabolism. Experimental phenylketonuria in infant monkeys: A high phenylalanine diet produces abnormalities simulating those of the hereditary disease. Transurethral resection of the prostate, serum glycine levels, and ocular evoked potentials. The assessment of protein nutrition and metabolism in the whole animal, with special reference to man. Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. Threonine requirement in young men determined by indicator amino acid oxidation with use of L-[1-13C]- phenylalanine. The effects of monosodium glutamate in adults with asthma who perceive themselves to be monosodium glutamate-intolerant. Carbohydrate craving in obese people: Suppression by treatments affecting serotoninergic transmission. Effect of excessive levels of lysine and threonine on the metabolism of these amino acids in rats. Capacity of the Chilean mixed diet to meet the protein and energy requirements of young adult males. The monosodium glutamate symptom complex: Assessment in a double-blind, placebo-controlled, random- ized study. Effect of dietary administration of monoso- dium L-glutamate on growth and reproductive functions in mice. Effect of tryptophan administration on tryptophan, 5- hydroxyindoleacetic acid and indoleacetic acid in human lumbar and cister- nal cerebrospinal fluid. Kinetics of human amino acid metabolism: Nutritional implications and some lessons. Nitrogen and amino acid requirements: The Massa- chusetts Institute of Technology Amino Acid Requirement Pattern. Current concepts concerning indispensable amino acid needs in adults and their implications for international nutrition plan- ning. Estimate of loss of labile body nitro- gen during acute protein deprivation in young adults. Plasma amino acid response curve and amino acid requirements in young men: Valine and lysine. Protein requirements of man: Efficiency of egg protein utilization at maintenance and sub-maintenance levels in young men. Protein requirements of man: Comparative nitrogen balance response within the submaintenance-to-maintenance range of intakes of wheat and beef proteins. Total human body protein synthesis in relation to protein requirements at various ages. Evaluation of the protein quality of an isolated soy protein in young men: Relative nitrogen requirements and effect of methionine supplementation. Leucine kinetics during three weeks at submaintenance-to-maintenance intakes of leucine in men: Adaptation and accommodation.

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One will notice that as more and more variables are added arteria epigastrica superficialis order discount toprol xl on-line, the number of patients in each cell of every 2 × 2 table gets smaller and smaller blood pressure medication young age buy toprol xl 50 mg overnight delivery. This will result in the confidence intervals of each odds ratio or relative risk getting larger and larger prehypertension in 30s cheap toprol xl 100 mg buy line. Some studies will look at multiple risk factors to determine which are most important in making a diagnosis or predicting the outcome of a disease. Although this can suggest which variables are most important, those important variables should be 1 Demonstrated to me by Karen Rossnagel from the Institute of Social Medicine, Epidemiology and Health Economics of the Charite´ University Medical Center in Berlin, Germany. The important variables are referred to as the derivation set and if the statistical significance found ini- tially is still present after the multivariate analysis, it is less likely to be due to a Type I error. The researchers still need to do a follow-up or validation study to verify that the association did not occur purely by chance. Multivariate analy- sis can also be used for data dredging to confirm statistically significant results already found as a result of simple analysis of multiple variables. Finally, multi- variate analysis can combine variables and measure the magnitude of effect of different combinations of variables on the outcome. There are four basic types of multivariate analysis depending on the type of outcome variable. Multiple linear regression analysis is used when the outcome variable is continuous. Multiple logistic regression analysis is used when the outcome variable is a binary event like alive vs dead, or disease-free vs recur- rent disease. Discriminant function analysis is used when the outcome variable is categorical such as better, worse, or about the same. An example of this is the time to death relationship between risk and or time to tumor recurrence among treated cancer patients. Assumptions and limitations There are several types of problems associated with the interpretation of the results of multivariate analysis. These include overfitting, underfitting, linerarity, interaction, concomitance, coding, and outliers. All of these can produce error during the process of adjustment and should be considered by the author of the study. Overfitting occurs when too many independent variables allow the researcher to find a relationship when in fact none exists. If there are 15 baseline characteristics considered as independent variables, it is likely that one or two will cause a result which has statistical significance by chance alone. As a rule of thumb, there should be at least 10, and some statisticians say at least 20, outcome events per independent vari- able of importance for statistical tests to be valid. In the example here, with only 20 outcome events, adjustment for one or at most two independent variables is all that should be done. Overfitting of variables is characterized by large confidence intervals for each outcome measure. A % surviving B Time Underfitting occurs when there are too few outcome events to find a differ- ence that actually exists. For example, a study of cigarette smokers followed 200 patients of whom two got lung cancer over 10 years. This may not have been long enough time to fol- low the cohort and the number of cancer cases is too small to find a rela- tionship between smoking and lung cancer. Too few cases of the outcome of interest may make it impossible to find any statistical relationship with any of the independent variables. Like overfitting, underfitting of variables is also characterized by large confidence intervals. To minimize the effects of underfitting, the sample size should be large enough for there to be at least 10 and preferably 20 outcome events for each independent variable chosen. Linearity assumes that a linear relationship exists between the independent and dependent variables, and this is not always true. Linearity means that a change in the independent variable always produces the same propor- tional change in the dependent variable.

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They can hypertension 2 order 100 mg toprol xl with amex, for example heart attack versus heartburn toprol xl 100 mg for sale, be readily controlled so that causal relationships can be recognized hypertension synonym discount toprol xl 100 mg buy. The effects of chronic exposures can be identified in far less time than they can with the use of epidemio- logical methods. All these advantages of animal data, however, may not always overcome the fact that species differences in response to chemical substances can sometimes be profound, and any extrapolation of animal data to predict human response needs to take this possibility into account. Key issues that are addressed in the data evaluation of human and animal studies are described below (see Box 4-1). Evidence of Adverse Effects in Humans The hazard identification step involves the examination of human, animal, and in vitro published evidence that addresses the likelihood of a nutrient eliciting an adverse effect in humans. Decisions about which observed effects are adverse are based on scientific judgment. Although toxicologists generally regard any demonstrable structural or functional alteration as representing an adverse effect, some alterations may be con- sidered to be of little or self-limiting biological importance. As noted ear- lier, adverse nutrient–nutrient interactions are considered in the defini- tion of an adverse effect. As explained in Chapter 2, the criteria of Hill (1971) are considered in judging the causal significance of an exposure–effect association indicated by epidemiological studies. Relevance of Experimental Data Consideration of the following issues can be useful in assessing the relevance of experimental data. Some animal data may be of limited utility in judging the toxicity of nutrients because of highly variable interspecies differences in nutrient requirements. Nevertheless, relevant animal data are consid- ered in the hazard identification and dose–response assessment steps where applicable, and, in general, they are used for hazard identification unless there are data demonstrating they are not relevant to humans, or it is clear that the available human data are sufficient. Data derived from studies involving parenteral, inhalation, or dermal routes of exposure may be considered relevant if the adverse effects are systemic and data are available to permit interroute extrapolation. Because the magnitude, duration, and frequency of exposure can vary considerably in different situations, consideration needs to be given to the relevance of the exposure scenario (e. Such data may provide significant information regarding the interspecies differences and similarities in 2The terms route of exposure and route of intake refer to how a substance enters the body (e. These terms should not be confused with form of intake, which refers to the medium or vehicle used (e. They may also assist in identifying life stage differences in response to nutrient toxicity. In some cases, there may be limited or even no significant data relating to nutrient toxicity. Thus, if there are significant pharmacokinetic and metabolic data over the range of intakes that meet nutrient requirements, and if it is shown that this pattern of pharmacokinetic and metabolic data does not change in the range of intakes greater than those required for nutrition, it may be possible to infer the absence of toxic risk in this range. In contrast, an alteration of pharmacokinetics or metabolism may suggest the poten- tial for adverse effects. Mechanisms of Toxic Action Knowledge of molecular and cellular events underlying the produc- tion of toxicity can assist in dealing with the problems of extrapolation between species and from high to low doses. It may also aid in understand- ing whether the mechanisms associated with toxicity are those associated with deficiency. In most cases, however, because knowledge of the bio- chemical sequence of events resulting from toxicity and deficiency is still incomplete, it is not yet possible to state with certainty whether these sequences share a common pathway. Quality and Completeness of the Database The scientific quality and quantity of the database are evaluated. Human or animal data are reviewed for suggestions that the nutrient has the potential to produce additional adverse health effects. Some highly sensitive subpopulations have responses (in terms of incidence, severity, or both) to the agent of interest that are clearly distinct from the responses expected for the healthy population. Selecting the critical data set includes the following considerations: • Human data, when adequate to evaluate adverse effects, are prefer- able to animal data, although the latter may provide useful supportive information. Pharmacokinetic, metabolic, and mechanistic data may be avail- able to assist in the identification of relevant animal species. When this is not possible, the differences in route of exposure are noted as a source of uncertainty.

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Second blood pressure ranges low order toprol xl paypal, the study was a clinical trial with the risk factors of race and gender being the independent variable and the refer- ral for catheterization blood pressure chart in europe discount 25 mg toprol xl otc, the dependent variable hypertension kidney infection discount toprol xl 100 mg on-line. Not only is the risk much smaller than reported in the news, but it approaches the null point suggesting lack of clinical significance or the possi- bility of a type I error. Ultimately, the original report using odds ratios led to a distortion in reporting of the study by the media. The effect of race and sex on physicians’ recom- mendations for cardiac catheterization. Misunderstandings about the effects of race and sex on physicians’ referrals for cardiac catheterization. Did the risk of the outcome increase with the quantity or duration of the exposure? Were patients similar for demo- graphics, severity, co-morbidity, and other prognostic factors? There is an excellent article by Hanley and Lippman- Hand that shows how to handle this eventuality. The maximum number of events that can be expected to occur when none have been observed is 3/n. One could expect to see as many as one adverse event in every 5 patients and still have come up with no events in the 14 patients in the initial study. The probability of no adverse events in one patient is 1 minus the probability of at least one adverse event in one patient. Another way of writing this is p(no adverse event in one patient) = 1–p(at least one adverse event in one patient). We can continue to reduce the actual adverse event rate to 1:10, and using the same process we get p(no adverse events in 14 patients) = (0. For example, studies of head-injured patients to date have shown that none of the 2700 low-risk patients, those with laceration only or bump without loss of consciousness, headache, vomiting, or change in neurological status, had any intracranial bleeding or swelling. Therefore, the largest risk of intracranial injury in these low-risk patients would be 3/2700 = 1/900 = 0. General observations on the nature of risk Most people don’t know how to make reasonable judgments about the nature of risk, even in terms of risks that they know they are exposed to . This was articu- lated in 1662 by the Port Royal monks in their treatise about the nature of risk. There 154 Essential Evidence-Based Medicine Table 13. People are more likely to risk a poor outcome if due to voluntary action rather than imposed action. They are likely to smoke and accept the associated risks because they think it is their choice rather than an addiction. Similarly, they will accept risks that they feel they have control over rather than risks controlled by others. Because of this, people are much more likely to be very upset when they find out that their medication causes a very uncommon, but previously known, side effect. One only has to read the newspapers to know that there are more stories on the front page about catastrophic accidents like plane crashes or fatal automo- bile accidents than minor automobile accidents. Patients are more willing to accept the risk of death from cancer or sudden cardiac death than death due to unforeseen complications of routine surgery. If there is a clear benefit to avoiding a particular risk, for example that one shouldn’t drink poison, patients are more likely to accept a bad outcome if they engage in that risky behavior. A major exception to this rule is cigarette smoking, because of the social nature of smoking and the addictive nature of nicotine. They are more willing to accept risk that is distributed to all people rather than risk that is biased to some people. There is a perception that man-made objects ought not to fail, while if there is a natu- ral disaster it is God’s will. Risk that is generated by someone in a position of Risk assessment 155 trust such as a doctor is less acceptable than that generated by someone not in that position like one’s neighbor. We are more accepting of risks that are likely to affect adults than of those primarily affecting children, risks that are more familiar over those that are more exotic, and random events like being struck by lightning rather than catastrophes such as a storm without adequate warning. Irving Fisher, Professor of Economics, Yale University, 1929 Learning objectives In this chapter you will learn: r the essential features of multivariate analysis r the different types of multivariate analysis r the limitations of multivariate analysis r the concept of propensity scoring r the Yule–Simpson paradox Studies of risk often look at situations where there are multiple risk factors asso- ciated with a single outcome, which makes it hard to determine whether a sin- gle statistically significant result is a chance occurrence or a true association between cause and effect.

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Exotic animal disease contingency framework plan: covering exotic notifiable animal diseases of livestock hypertension bench discount toprol xl 50 mg buy. Chapter 4 blood pressure 14080 100 mg toprol xl buy visa, Field manual of wildlife diseases: general field procedures and diseases of birds heart attack what everyone else calls fun buy toprol xl 100 mg amex. The specific actions required to reduce risks associated with these diseases should be identified within risk assessments [►Section 3. More generally, ‘healthy habitat management’ and reducing stressors at a site will benefit disease prevention and/or control [►Section 3. Additionally, following standardised protocols for releasing and moving animals into, within and out of wetlands will help to mitigate disease risks [►Section 3. It is important that wetland managers identify stressor risks within their site and the broader catchment/landscape, and understand that these may change over time. Once these factors are identified, they can be managed and/or their impact mitigated, as appropriate. Disease zoning (although challenging in wildlife and/or aquatic systems) can help control some infectious diseases through the delineation of infected and uninfected zones defined by sub-populations with different disease status. Buffer zones separating infected and uninfected zones may consist of physical barriers, an absence of hosts, an absence of disease vectors or only immune hosts e. Appropriate levels of surveillance are required to accurately define zones and for prevention of disease spread to occur, the movements of animals between zones needs to be restricted. The movement of infected animals to new areas and populations represents the most obvious potential route for introduction of new/novel infections. The risk of transmission and spread of disease can be minimised by conducting risk assessments and following certain standardised national and international guidelines and regulations for moving, relocating and/or releasing animals. A disease risk analysis should be conducted for any translocations for conservation purposes. Biosecurity in wetlands refers to the precautions taken to minimise the risk of introducing infection (or invasive alien species) to a previously uninfected site and, therefore, preventing further spread. Infectious animal diseases are spread not only through movement of infected hosts but also their products e. Constructed treatment wetlands can assist greatly in reducing risks from contaminated wastewaters. Where possible, biosecurity measures should be implemented routinely as standard practice whether or not an outbreak has been detected. A regional/supra-national approach to biosecurity is important for trans-boundary diseases, particularly those where domestic and international trade are considered as important pathways for disease spread, e. If wetland stakeholders understand the principles and value of biosecurity and what measures to take, this will encourage the development of an everyday ‘culture’ of biosecurity which can help disease prevention and control. Implementing biosecurity measures in the natural environment can be extremely challenging, particularly in aquatic systems, and although eliminating risk will be impossible, a substantial reduction in risk may be achievable, particularly where several complementary measures are employed. Stressors may not in themselves cause disease but their effects can be subtle and can influence disease dynamics and the likelihood of a disease outbreak. Stressors can be additive or synergistic, working together to shift the balance between health and disease within individual hosts or populations. Consequently, stressors at wetland sites should be identified and managed to reduce disease susceptibility. Identification of potential stressors requires a thorough knowledge of the site and a reasonable understanding of the biology and ecology of the animal species present. It is important to periodically re-assess the stressors at a given site as they may change over time. Nutrition: malnutrition (deficiency, excess or imbalance of nutrients) of animals may result in increased disease susceptibility. Consideration can be given to providing supplementary high quality food and/or water, although artificial provisioning brings its own disease risks (e. Human disturbance: ideally this should be reduced/kept to a minimum where possible, especially at sensitive times in the life cycles of wildlife, at times when other stressors are known to occur or when risks of disease outbreaks are high. Zoning human activities such as recreation and agriculture may also be of value in managing human disturbance. Predators: depending on the management priorities of a site, measures could be considered to minimise stress from predators (e. Interspecific and intraspecific competition: depending on the management priorities of a site, measures could be considered to reduce competition from other animals (e.

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Such a New Taxonomy would x Describe and define diseases based on their intrinsic biology in addition to traditional physical “signs and symptoms blood pressure of 120/80 generic 50 mg toprol xl with mastercard. The informational infrastructure required to create a New Taxonomy with the characteristics described above overlaps with that required to modernize many other facets of biomedical research and patient care blood pressure wrist band buy cheap toprol xl 50 mg online. This infrastructure requires an “Information Commons” in which data on large populations of patients become broadly available for research use and a “Knowledge Network” that adds value to these data by highlighting their interconnectedness and integrating them with evolving knowledge of fundamental biological processes pulse pressure less than 10 order toprol xl 50 mg on-line. New models for population-based research will enable development of the Knowledge Network and New Taxonomy. Current population-based studies of disease are relatively inefficient and can generate conclusions that are not relevant to broader populations. Widespread incorporation of electronic medical records into the health-care system will make it possible to conduct such research at “point-of-care” in conjunction with the routine delivery of medical services. Moreover, only if the linked phenotypic data is acquired in the ordinary course of clinical care is it likely to be economically feasible to characterize a sufficient number of patients and ultimately to create a self-sustaining system (i. Redirection of resources could facilitate development of the Knowledge Network of Disease. The initiative to develop a New Taxonomy—and its underlying Information Commons and Knowledge Network—is a needed modernization of current approaches to integrating molecular, environmental, and phenotypic data, not an “add-on” to existing research programs. Enormous efforts are already underway to achieve many of the goals of this report. In the Committee’s view, what is missing is a system-wide emphasis on shifting the large-scale acquisition of molecular data to point-of-care settings and the coordination required to insure that the products of the research will coalesce into an Information Commons and Knowledge Network from which a New Taxonomy (and many other benefits) can be derived. In view of this conclusion, the Committee makes no recommendations about the resource requirements of the new-taxonomy initiative. Obviously, the process could be accelerated with new resources; however, the basic thrust of the Committee’s recommendations could be pursued by redirection of resources already dedicated to increasing the medical utility of large-scale molecular data-sets on individual patients. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 5 Recommendations To create a New Taxonomy and its underlying Information Commons and Knowledge Network, the Committee recommends the following: 1. Pilot observational studies should be conducted in the heath care setting to assess the feasibility of integrating molecular parameters with medical histories and health outcomes in the ordinary course of clinical care. These studies would address the practical and ethical challenges involved in creating, linking, and making broadly accessible the datasets that would underlie the New Taxonomy. Best practices defined by the pilot studies should then be expanded in scope and scale to produce an Information Commons and Knowledge Network that are adequately powered to support a New Taxonomy. As this process evolves, there should be ongoing assessment of the extent to which these new informational resources actually contribute to improved health outcomes and to more cost effective delivery of health care. As data from point-of- care pilot studies, linked to individual patients, begin to populate the Information Commons, substantial effort should go into integrating these data with the results of basic biomedical research in order to create a dynamic, interactive Knowledge Network. This network, and the Information Commons itself, should leverage state-of-the-art information technology to provide multiple views of the data, as appropriate to the varying needs of different users (e. Initiate a process within an appropriate federal agency to assess the privacy issues associated with the research required to create the Information Commons. Because these issues have been studied extensively, this process need not start from scratch. However, in practical terms, investigators who wish to participate in the pilot studies discussed above—and the Institutional Review Boards who must approve their human- subjects protocols— will need specific guidance on the range of informed-consent processes appropriate for these projects. Subject to the constraints of current law and prevailing ethical standards, the Committee encourages as much flexibility as possible the guidance provided. As much as possible, on-the-ground experience in pilot projects carried out in diverse health-care settings, rather than top-down dictates, should govern the emergence of best practices in this sensitive area, whose handling will have a make- or-break influence on the entire information-commons/knowledge-network/new- taxonomy initiative. Inclusion in these deliberations of health-care providers, payers, and other stakeholders outside the academic community will be essential. Widespread data sharing is critical to the success of each stage of the process by which the Committee envisions creating a New Taxonomy. Most fundamentally, the molecular and phenotypic data on individual patients that populate the Information Commons must be broadly accessible so that a wide diversity of researchers can mine them for specific purposes and explore alternate ways of deriving Knowledge Networks and disease taxonomies from them. Current standards developed and adopted by federally sponsored genome projects have addressed some of these issues, but substantial barriers, particularly to the sharing of phenotypic and health-outcomes data on individual patients, remain. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 6 Commons.

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There are data that show the benefits of certain Dietary and Functional Fibers on gastro- intestinal health blood pressure ranges too low best buy for toprol xl, including the effect of fiber on duodenal ulcers arteria peronea magna generic toprol xl 25 mg on line, consti- pation hypertension disorder toprol xl 25 mg buy mastercard, laxation, fecal weight, energy source for the colon, and prevention of diverticular disease. For duodenal ulcer and diverticular disease, the data are promising for a protective effect, but insufficient data exist at this time upon which to base a recommended intake level. It is clear that fiber fermentation products provide energy for colonocytes and other cells of the body, but again this is not sufficient to use as a basis for a recommen- dation for fiber intake. With regard to the known fecal bulking and laxative effects of certain fibers, these are very well documented in numerous studies. Epidemiological Studies Thun and coworkers (1992) found a significant inverse relation between the intake of citrus fruits, vegetables, and high fiber grains and colon cancer, although Dietary Fiber intake was not specifically analyzed. Fuchs and colleagues (1999) prospectively examined the relationship between Dietary Fiber intake and the risk of colon cancer in a large cohort of women. The same study group found a minimal nonsignificant inverse association in an earlier report that was based on 150 cases of colon cancer reported during 6 years of follow-up (Willett et al. Likewise, in six large, prospective studies, inverse associations between Dietary Fiber intake and the risk of colon cancer were weak or nonexistent (Giovannucci et al. Inverse relationships have been reported between Dietary Fiber intake and risk of colon cancer in some case-control studies (Bidoli et al. A critical review of 37 observational epide- miological studies and a meta-analysis of 23 case-control studies showed that the majority suggest that Dietary Fiber is protective against colon cancer, with an odds ratio of 0. Furthermore, a meta-analysis of case-control studies demonstrated a combined relative risk of 0. Lanza (1990) reviewed 48 epidemiological studies on the relationship between diets containing Total Fiber and colon cancer and found that 38 reported an inverse relationship, 7 reported no association, and 3 reported a direct association. In the Netherlands, Dietary Fiber intake was reported to be inversely related to total cancer deaths, as the 10-year cancer death rate was approximately threefold higher in individuals with low fiber intake compared with high fiber intake (Kromhout et al. Intervention Studies There have been a number of small clinical interventions addressing various surrogate markers for colon cancer, primarily changes in rectal cell proliferation and polyp recurrence. Generally, the small intervention trials have shown either no effect of fiber on the marker of choice or a very small effect. There was no overall decrease in rectal cell proliferation as a result of fiber supple- mentation unless the groups were divided into those with initially high and those with initially normal labeling indices. With this statistical division, there was a significant decrease in cell proliferation as a result of the fiber supplementation in six of the eight patients with initially high labeling indices and three of the eight patients with initially low indices, which suggests that wheat-bran fiber is protective against colon cancer. In a sepa- rate trial from the same group, supplemental dietary wheat-bran fiber (2. Additionally, two randomized, placebo-controlled trials found no significant reduction in the incidence of colon tumor indicators among subjects who supplemented their diet with wheat bran or consumed high fiber diets (MacLennan et al. Recently, findings from three major trials on fiber and colonic polyp recurrence were reported (Alberts et al. All were well-designed, well-executed trials in indi- viduals who previously had polyps removed. The Polyp Prevention Trial, which incorporated eight clinical centers, included an intervention that consisted of a diet that was low in fat, high in fiber, and high in fruits and vegetables (Dietary Fiber) (Schatzkin et al. There was no difference in polyp recurrence between the intervention and control groups. Again, there was no differ- ence between the control group and the intervention group in terms of polyp recurrence. The adjusted odds ratio for the psyllium fiber intervention on polyp recurrence was 1. Potential Mechanisms Many hypotheses have been proposed as to how fiber might protect against colon cancer development; these hypotheses have been tested primarily in animal models. The hypotheses include the dilution of car- cinogens, procarcinogens, and tumor promoters in a bulky stool; a more rapid rate of transit through the colon with high fiber diets; a reduction in the ratio of secondary bile acids to primary bile acids by acidifying colonic contents; the production of butyrate from the fermentation of dietary fiber by the colonic microflora; and the reduction of ammonia, which is known to be toxic to cells (Harris and Ferguson, 1993; Jacobs, 1986; Klurfeld, 1992; Van Munster and Nagengast, 1993; Visek, 1978). Unfortunately, most of the epidemiological and even the clinical intervention trials did not measure functional aspects of potential mechanisms by which fiber may be protective, and they did not attempt to relate aspects of colon physiology such as fecal weight or transit time to a protective effect against tumor development. Cummings and colleagues (1992) suggest that a daily fecal weight greater than 150 g is protective against colon cancer. In a study by Birkett and coworkers (1997), it was necessary to achieve a stool weight of 150 g to improve fecal markers for colon cancer, including fecal bulk, primary to secondary bile acid ratios, fecal pH, ammonia, and transit time. Dietary Fiber intake was 18 ± 8 g in the less than 150-g fecal-weight group and 28 ± 9 g in the greater than 150-g group (p < 0.

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Although no clear beneft could be demonstrated in clini- proactive family care conferences to identify advanced direc- cal trials with supplemental glutamine heart attack alley 50 mg toprol xl buy otc, there is no sign of harm blood pressure chart software buy cheap toprol xl 100 mg line. However arrhythmia forum buy generic toprol xl 25 mg on line, only one study was in tion; open fexible visitation; family presence during clinical septic patients (471), none was individually powered for mortal- rounds and resuscitation; and attention to cultural and spiri- ity (472, 473), and all three used a diet with high omega-6 lipid tual support (495). Additionally, the integration of advanced content in the control group, which is not the usual standard of care planning and palliative care focused on pain manage- care in the critically ill. The authors who frst reported reduced ment, symptom control, and family support has been shown mortality in sepsis (471) conducted a follow-up multicenter to improve symptom management and patient comfort, and study and again found improvement in nonmortality outcomes, to improve family communication (484, 490, 496). Setting Goals of Care is 2% in previously healthy children and 8% in chronically ill chil- 1. We recommend that goals of care and prognosis be dis- dren in the United States (497). Defnitions of sepsis, severe sepsis, cussed with patients and families (grade 1B). We recommend that the goals of care be incorporated into are similar to adult defnitions but depend on age-specifc heart treatment and end-of-life care planning, utilizing palliative rate, respiratory rate, and white blood cell count cutoff values care principles where appropriate (grade 1B). We suggest starting with oxygen administered by face mask patients with multiple organ system failure or severe neu- or, if needed and available, high-fow nasal cannula oxy- rologic injuries will not survive or will have a poor quality gen or nasopharyngeal continuous positive airway pressure of life. Peripheral treatments or to withdraw life-sustaining treatments in these intravenous access or intraosseous access can be used for fuid patients may be in the patient’s best interest and may be what resuscitation and inotrope infusion when a central line is not patients and their families desire (481). If mechanical ventilation is required, then cardio- ferent end-of-life practices based on their region of practice, vascular instability during intubation is less likely after appro- culture, and religion (482). Models for structuring initiatives to enhance care bation; however, during intubation and mechanical ventilation, Critical Care Medicine www. For improved circulation, peripheral intravenous access or intraosseus access can be used for fuid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required then cardiovascular instability during intubation is less likely after appropriate cardiovascular resuscitation (grade 2C). Initial therapeutic end points of resuscitation of septic shock: capillary refll of ≤2 secs, normal blood pressure for age, normal pulses with no differential between peripheral and central pulses, warm extremities, urine output >1 mL·kg-1·hr-1, and normal mental status. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock (grade 1C). Empiric antibiotics be administered within 1 hr of the identifcation of severe sepsis. Blood cultures should be obtained before administering antibiotics when possible but this should not delay administration of antibiotics. Clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension (grade 2D). Clostridium diffcile colitis should be treated with enteral antibiotics if tolerated. In the industrialized world with access to inotropes and mechanical ventilation, initial resuscitation of hypovolemic shock begins with infusion of isotonic crystalloids or albumin with boluses of up to 20 mL/kg crystalloids (or albumin equivalent ) over 5–10 minutes, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refll, peripheral pulses, and level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales exist then inotropic support should be implemented, not fuid resuscitation. In non-hypotensive children with severe hemolytic anemia (severe malaria or sickle cell crises) blood transfusion is considered superior to crystalloid or albumin bolusing (grade 2C). Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fuid resuscitation (grade 2C). Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure be given vasodilator therapies in addition to inotropes (grade 2C). Timely hydrocortisone therapy in children with fuid refractory, catecholamine resistant shock and suspected or proven absolute (classic) adrenal insuffciency (grade 1A). Protein C and Activated Protein Concentrate No recommendation as no longer available. During resuscitation of low superior vena cava oxygen saturation shock (< 70%), hemoglobin levels of 10 g/dL are targeted. After stabilization and recovery from shock and hypoxemia then a lower target > 7. Use plasma therapies in children to correct sepsis-induced thrombotic purpura disorders, including progressive disseminated intravascular coagulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura (grade 2C). We recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with sepsis (grade 1D).

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All of these drugs except telithromycin had been approved for marketing for more than 15 years and 63% for more than 35 years [9] arrhythmia 2014 ascoms 50 mg toprol xl order fast delivery. The most common types of drugs were antimicrobials among 33% of the drugs arteria gastroepiploica toprol xl 100 mg purchase with mastercard, followed by drugs acting on the central nervous system (12 prehypertension fatigue buy generic toprol xl 25 mg on line. Although antimicrobials were the most common agents among drugs, antimicrobials were also the most common agents in categories B (30%), C (19%) and D (27%). There is unfortunately not enough room to discuss many of these well-documented hepatotoxic agents. As mentioned in the abstract, azathioprine and infliximab have in one study been found to be associated with the highest risk of liver injury [9]. Both hepatocellular and cholestatic injury has been described due to azathioprine [8,9]. Despite the common problem of hepatotoxicity with azathioprine, there is a lack of studies with a significant number of well-characterized patients with this type of liver injury. Drugs that, according to analysis of data in LiverTox [8], have been associated with more than 100 cases of drug-induced liver injury. This seems particularly true for drugs with reports of documented rechallenge, which had been reported in at least one case in 38% of the drugs [9]. In comparison with category A drugs, which almost exclusively had been associated with fatality, approximately 50% of category B drugs had been associated with a fatal outcome. Thus, in drugs with less frequent reporting of liver injury in category B, only 38% had rechallenge reported vs. Drugs in category B (>12 and >40 cases) that, according to analysis of data in LiverTox [8], have been associated with >30 published case reports of drug induced liver injury. Categories C, D and E Overall, 222/353 (63%) of drugs in LiverTox® with hepatotoxicity fall into categories C and D. Compared with category D, with only one to three cases reported, category C (<12 and >4 case reports) drugs were more likely to have rechallenge reports, with 26% vs. A positive rechallenge is usually defined with biochemical criteria, showing recurrence of liver test abnormalities upon readministration of the drug, due to either intentional or inadvertent re-exposure [4,5]. This is generally considered to be the gold standard of the diagnosis of drug-induced liver injury. A documented positive rechallenge provides more evidence of the hepatotoxicity of a Int. Given the frequency of case reports with drugs in categories A and B, there seems little doubt that drugs in these categories can lead to hepatotoxicity and little need to do a strict causality assessment of reports with these drugs. However, in category C, consisting of 4–11 case reports, the hepatotoxicity of some drugs can be put into question. Thus, it can be concluded that these drugs do not have a well-documented hepatotoxicity, although liver injury with their use cannot be excluded. The poorly documented exclusion of competing causes, as well as the use of other concomitant drugs, made a causality assessment difficult. It is very important that observations of hepatotoxicity of new drugs should lead to well-documented case reports with detailed clinical and biochemical information. Table 3 illustrates the five most common drugs associated with liver injury in at least three prospective studies. In India, anti-tuberculous drugs (58%), anti-epileptics (11%), olanzapine (5%), and dapsone (5%) were the most common causes [16]. The 10 most frequently implicated drugs were: amoxicillin-clavulanate, flucloxacillin, erythromycin, diclofenac, sulfamethoxazole/Trimethoprim, isoniazid, disulfiram, Ibuprofen and flutamide [12–14,21]. Drugs with an intermediate risk were amoxicillin-clavulanic acid and cimetidine, with a risk of one per 10 per 100,000 users [24]. The limitations of this study were the retrospective design with a lack of complete data regarding diagnostic testing and a lack of data on over-the-counter drugs and herbal agents [24]. Amoxicillin-clavulanate-induced liver injury was found in one of 2350 outpatient users, which was higher among those who were hospitalized already, one of 729. This might be due to a detection bias, with more routine testing of the liver in the hospital, but it cannot be excluded that sicker patients are more susceptible to liver injury from this drug. The incidence rates were higher than previously reported, with the highest being one of 133 users for azathioprine and one of 148 for infliximab. Acknowledgments: No specific grants were obtained for research work presented in this paper and no funds for publishing in open access. Discrepancies in liver disease labeling in the package inserts of commonly prescribed medications.

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The practice of medicine is marked by moral pluralism blood pressure medication ed toprol xl 25 mg purchase, relativism blood pressure medication grapefruit juice generic toprol xl 100 mg buy, and the privatization of morality arteria technologies discount toprol xl 100 mg. In the face of these challenges, Pellegrino calls physicians to an act of profession that can tie them to their engage- ment in healing, so that they can come to appreciate professional virtue in terms of the telos of the clinical encounter: the patient’s good. Pellegrino lists among the virtues that should mark the good physician: fdelity to trust and promise, benevolence, efacement of self-interest, compassion and caring, intellectual honesty, justice, and prudence. Having spoken to professional virtue in the clinical context, Pel- legrino turns in the next essay to challenges to the physician’s moral con- science. His focus is on the conficts engendered as a result of practicing medicine in an often afrmatively secular culture. This tension is rooted in the circumstance that traditional Christians know things about medical morality unrecognized within secular society. In “The Physician’s Con- science, Conscience Clauses, and Religious Belief: A Catholic Perspec- tive,” Pellegrino lays out a geography of some of the resulting moral conficts, giving special attention to the rising reluctance of the state and others to confront honestly what should count as violations of conscience. For example, although religious exemption laws and conscience clauses have protected physicians from being directly coerced to engage in abor- tion or physician-assisted suicide, there is nevertheless often a require- ment that they refer patients to others to do things the Christian physician knows to be immoral (that is, since abortion is equivalent to murder, then referring a woman to an abortionist is equivalent to referring someone to the services of a hit man, even if one will not engage directly in the mur- der oneself). In addition, there are growing constraints on religious insti- tutions, once they receive tax funds, to provide services they would recognize as immoral, though their co-religionists have been forced to pay those very taxes. Among the failures in such public policy approaches is © 2008 University of Notre Dame Press An Introduction not appreciating that institutions, in order to maintain an integrity and commitment to virtue, must preserve the character of their commitments to the particular communities that brought them into existence and sus- tain them. It is through institutions such as sectarian hospitals that indi- viduals realize their concrete lives in moral communities, with the result that the moral integrity of the individual is put at jeopardy if they are not able to protect and maintain the moral character and integrity of their institutions and their moral communities. The last section ofers Pellegrino’s analysis of the ambiguities of hu- manism, the limitations of the Hippocratic Oath, and the challenges to framing a medical ethics for the future. The frst subsection, “Humanities in Medicine,” brings together essays exploring the role of humanism in medicine and medical education. The frst essay, “The Most Humane of the Sciences, the Most Scientifc of the Humanities,” already partially quoted in this introduction, is an early manifesto that in many ways in- spired the development of humanities teaching in medical schools. It in- cludes Pellegrino’s famous synopsis of the relationship of humanities and medicine: “Medicine is the most humane of sciences, the most empiric of arts, and the most scientifc of humanities. Its subject matter is an ideal ground within which to develop the attitudes associated with the human- istic and liberally educated. As he stresses, the humanities have traditionally been recognized as quite diferent from the liberal arts. Pellegrino also stresses a point underscored by Abraham Flexner: “the pull toward specialization and scholarship” tends to transform the study of the humanities from the pursuit of wis- dom to the pursuit of information and pedantry. This point is developed further in the second essay, “The Humanities in Medical Education: Entering the Post-Evangelical Era,” where Pellegrino again emphasizes that the liberal arts, from classical times, have compassed “the intellectual skills needed to be a free man. The humani- ties must be made integral to the life of the medical student and the physi- cian. In actual practice, medical students and physicians must see how the medical humanities support the physician’s virtuous response to actual patients. The next essay locates concerns regarding humanism and the virtue of the physician in the context of Roman Catholic perspectives on medical morality. In “Agape and Ethics: Some Refections on Medical Morals from a Catholic Christian Perspective,” Pellegrino reviews the recent Roman Catholic dialogue with “the dominant cultural ideas of the time” and the competing accounts of morality and ethics which this has produced. He selects for his focus what he terms an agapeistic ethic: a virtue-based ethic which afrms charity as the principle that should structure the relation- ship between physicians and patients. With charity taken as the ordering principle of discernment in moral choice, Pellegrino places the general concerns of the humanities and the liberal arts within the more concrete focus of a particular Roman Catholic understanding. In this fashion, he gives content to the meaning of the virtuous and humane physician. He suggests as well the importance of the tie between Christian belief and vir- tuous practice. This section ends with an essay that locates the previous discussions in terms of the challenge of bringing bioethics to speak to the pressing issues of normative ethics: “Bioethics at Century’s Turn: Can Normative Ethics Be Retrieved?

Kulak, 52 years: Doing electives and speaking surgeon, a neurosurgeon and a physiatrist working together in with others in similar situations will help, but a month of being a specialized clinic. To achieve this reduction, the Commission pointed out “the value of adequate training in radiological protection for all persons who administer radiation exposures to patients” (para. Do doctors look after their health as well as play in sustaining the health of fellow health professionals, their patients?

Candela, 25 years: Probability is what we are estimat- ing when we select a pretest probability of disease for our patient. Thus, as recovery of body weight proceeds, the energy requirement will vary not only as a function of body weight but in response to changes in body composition. This is known as de-facto rationing and is man- ifested by long waiting times in a municipal hospital emergency department or for an appointment to be examined by a specialist or get diagnostic studies done.

Nasib, 38 years: Despite advances in technology, these are still Renal biopsy is indicated when glomerular disease is sus- unable to completely mimic renal function, and none pected,andinunexplainedacuterenalfailure. A curriculum of basic medi- cal texts to be used for introductory instruction seems to have formed just after . The two primary contexts are the evaluation of research proposals and manuscript reviews for journals.

Koraz, 40 years: The blacksmith – he had been an auto mechanic who shoed horses on the side – but he was the blacksmith now. National Vaccine Advisory Committee recommendations for federal adult immunization programs regarding im- munization delivery, assessment, research, and safety monitoring. It appears that these relaxation times changes when going from normal to pathological tissue – and this can be used in diagnostics.

Jorn, 64 years: Chronic renal failure occurs in a substantial glomerulosclerosis, occasionally leading to renal fail- number of patients. In countries with established chronic disease problems, additional measures will be required, not only to prevent disease, but also to manage illness and disability. Neurolog- ical signs, papilloedema and retinal haemorrhages may Prognosis be present.

Ingvar, 30 years: Fixed-dose combinations As many high-risk patients would benefit from treatment with several drugs proven to reduce cardiovascular disease, the notion of a combination pill, using fixed-dose formulations of effective drugs, was originally proposed to overcome two problems: the difficulty of adherence to treatment involving multiple pills; and the inadequate dosages often prescribed in routine clinical practice (384). Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Recipe mirte, geneste, gallitrici, et in aceto coquea ad aceti consumptionem, et ex eo assidue extrema capillorum frica.

Agenak, 55 years: Working with health plans, Vivius provides employees a personal web page that enables them to select their own physicians based on their stated rates. Every five years the Federal government issues dietary guidelines that are intended to promote health and also satisfy food industry interests. The health insurance industry is waging a quiet struggle to preserve its options in the face of new genetic predictive tools.

Rocko, 49 years: It means patients would get a drug and the dosage exactly customized to their own genomic background. Imaging in breast disease Cytology from either procedure is graded into five cate- gories (see Table 10. Prevention  At time of treatment, wash items used in the past 48 hours in hot water and put them in a hot dryer.

Berek, 58 years: This has been reinforced recently with a study entitled Saving dollars versus saving lives, with the aim of justifying breast cancer screening with X ray mammography [13]. The emergence and re-emergence of diseases has become a wildlife conservation issue both in terms of the impact of the diseases themselves and of the actions taken to control them. Low hepatitis B knowledge among pe- rinatal healthcare providers serving county with nation’s highest rate of births to mothers chronically infected with hepatitis B.

Treslott, 65 years: This is a convoluted way of saying that it finds the alternative hypothesis to be false, when it ain’t! Ster- ile conditions, which pose a considerable technical challenge, are rarely necessary. When medical students first start doing this, it is useful to make the list as exhaustive as possible to avoid missing any diseases.

Baldar, 34 years: Mental status examination shows mild obtundation, blunted affect, and slow, incoherent speech. Key privacy and security factors influencing the integration of genomics into healthcare include consumer confidence regarding the privacy and security of their genetic infor- mation as it relates to their medical record. At the end of treatment, reduce doses gradually to avoid withdrawal syndrome or rebound effect; • in the event of overdose: ataxia, muscular weakness, hypotension, confusion, lethargy, respiratory depression, coma.

Zarkos, 62 years: Widespread in Africa, Bovine bovis; responsible for elevated mortality and Mycobacterium parts of Asia and some Middle Eastern N tuberculosis bovis morbidity in wild mammals in some protected countries. Indeed, the individual-centric character of the Information Commons—and the inclusion of available data about contributing individuals, including information about where and in what circumstances they live—offers an unprecedented path toward a Knowledge Network of Disease that can meet global needs for healthcare and disease prevention. Aetiology/pathophysiology 2 High anal fistulas have a track which extends above It is thought that sinuses arise from penetration of hairs the pectinate line below the anorectal ring.

Corwyn, 36 years: Earum igitur miseranda calamitas et maxime cuiusdamg mulieris gratia animum meum solli- citansh inpulit, ut circa egritudines earumi euidentius explanaremj earum sani- ¶a. The effect of a behaviour change intervention on the diets and physical activity levels of women attending Sure Start Children’s Centres: Results from a complex public health intervention. Duration – According to clinical response Contra-indications, adverse effects, precautions – Do not administer for other types of oedema, especially those due to kwashiorkor.

Gembak, 31 years: Despite advances in technology, these are still Renal biopsy is indicated when glomerular disease is sus- unable to completely mimic renal function, and none pected,andinunexplainedacuterenalfailure. After an abortion, samples should be collected from the placenta, vagina and foetal stomach. Timely hydrocortisone therapy in children with fuid refractory, catecholamine resistant shock and suspected or proven absolute (classic) adrenal insuffciency (grade 1A).

Peratur, 21 years: If one then repeats the study and gets exactly the same results with 25 patients in each group, then the result turns out to be statistically significant. The list of benefits from this practice is not insignificant: reducing medical risk; more efficiently fighting chronic disease; making better decisions about what care is needed; choosing doctors, hospitals, or benefit designs that meet the con- sumer’s specific needs; absorbing some of the health plan’s insurance risk (through defined-contribution care); and interacting with the health plan’s administrative systems. Figure 3-4 provides a recommended structure and content for such a plan (Ramsar Convention 2002).

Campa, 53 years: Measures to alter water flow include changing the dimensions, gradient and features of water channels. This will alter the information used in the analysis of time to occlusion with two different types of bypasses. Surrogate marker An outcome variable that is associated with the outcome of interest, but changes in this marker are not necessarily a direct measure of changes in the clinical outcome of interest.

Hamil, 56 years: The submission of the thesis (as per University regulations) on an agreed topic must normally be within 36 months of initial registration. The tables and figures in this Pocket Guide follow the numbering of the 2017 Global Strategy Report for reference consistency. Appreciate the fear and anxiety many patients have regarding even simple procedures.

Hassan, 47 years: Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C http://www. These values are obtained from studies of patient attitudes toward each of the outcomes in question and will be discussed in more detail shortly. Some hospital medical records are large enough to use for doorstops or weapons (an older person’s medical record has an impressive throw weight).

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