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Regular observation of employee behavior at emergency incidents and in the station is necessary to evaluate compliance with established protocols and work practices. All deficiencies noted should include recommendations for improvement and follow-up re-inspections. Equipment and Supplies Inventory All infection control equipment and supplies must be available. Employee interviews can be used to determine individual knowledge and acceptance of infection control protocols. Post incident analyses or individual debriefing after an emergency response can also help identify areas of confusion that can be addressed in counseling and/or training sessions. For example, an increase in response volume will require increased supplies and equipment. Monitoring compensation claims will help identify trends in injuries and exposures. Analysis of these claims can provide direction for possible training, behavior modification needs, and/or protocol changes. The department also should monitor community health trends to stay current on prevalent communicable diseases, potentially dangerous situations, etc. Monitoring community trends facilitates a proactive infection control response to unexpected threats. For example, if there is an outbreak of meningitis within the community, the department could take immediate early action to notify all members and implement more stringent infection control procedures. Confidentiality Maintaining the confidentiality of certain records is necessary for the protection of both employees and patients. Patient information should be released only to authorized individuals, and in accordance with current guidelines and regulations regarding patient privacy, need for consent, and (if a research study) approval of appropriate supervisory bodies. The records should include a copy of the authorization for release, the name of the individual receiving the information, the name of the individual releasing the information, and the dates involved. While exposure records may be used to evaluate the effectiveness of the program, the confidentiality of the members involved must be maintained. Written procedures should specify who has access to medical records and under what circumstances. The process by which medical information is collected, stored, retrieved, and released must be thought out carefully. Release of medical information should occur only with the written consent of the member. Date the written authorization expires It is critical that members? medical records are not disclosed or reported to any person within or outside the department except as required by law. Computer security must be designed to protect the confidentiality of patient and member medical records. This may require the use of passwords to limit access to a minimum of individuals. The department should take full advantage of legal resources available for guidance on statutory requirements related to confidentiality. Changes in laws/regulations or technology may require revisions in protocols or equipment related to infection control. Program revision may also be necessary when information analysis reveals lack of compliance of performance indicators. Laws/Regulations As stated earlier in this manual, it is critical that the infection control officer stay current on the laws/regulations governing infection control practices. Reviewing Morbidity Mortality Weekly on a regular basis is an excellent resource for finding changes in suggested practices and updating knowledge of infectious/communicable diseases. Establishing a relationship with local infection control specialists in hospitals is also a resource that should be helpful in maintaining up-to-date information. Non-compliance When compliance set for a performance indicator is not met, an analysis must be completed to determine the cause of the problem. For example, an infection control performance objective is that personnel will use body substance isolation techniques 100 percent of the time when there is potential exposure to any body fluid. A careful analysis might identify one or more of the following reasons for the non-compliance, each of which may require action steps at different levels of the system. From this limited example, it is obvious that analyzing causes of non-compliance involves the entire organization and system, including policymakers, line personnel, health and safety personnel, and others. The action plan should be specific, with exact steps necessary to assure compliance. The first decision that management must make is who will be on the team that develops the action plan. In addition to the infection control officer, the team should include representatives directly affected by the performance indicator, including line personnel. A timeframe for both the completion of the action plan and the accomplishment of the actions should be identified. Providing the team with a schedule and checkpoints for completion of the plan helps keep them on-task to reach a solution in an acceptable timeframe. In addition to identifying the specific steps necessary to correct the problem, two additional areas should be addressed when developing the action plan. First, obstacles that might impede the implementation of the plan should be identified. Implementing the Plan In addition to the obvious necessity of allocating resources, the biggest challenge during project implementation will be to maintain credibility and focus, and to maintain momentum among team members. Efficient use of the schedule will help concentrate efforts and attention where they are most needed. Monitor the Plan Once the plan is implemented, it is critical that the results of the implementation be monitored and evaluated to determine results or problems that arise. Monitoring and evaluation may take a variety of forms, depending on the actions specified in the plan. Methods to collect data to monitor results should be developed during the planning stage. It is important that the monitoring methods allow for timely feedback, so any problems will be detected early. If problems with the plan are detected during the monitoring phase, or if the action plan did not make a difference, it must be revised. Based on the problem identified, revision may require re-entering the process cycle at any point. Periodic evaluations ensure continued compliance with current standards and practices. Infection control data collection and analysis are critical for effective program evaluation, compliance/quality monitoring, and ongoing program management. Detailed records must be maintained in the areas of training, exposure, incidents, health, work practices, and equipment/supplies inventories. The department should seek a legal review of all program changes prior to implementation, since infection control programs deal with medical and legal issues and member safety. There are few services left where providers do not don protective gloves when dealing with patients. Although this concept usually is reinforced verbally, frequently it is accepted as being met when the student demonstrates the donning of gloves only. It is a well-known educational fact that the way we learn a process/skill in the training environment is the way we tend to carry that process out in real life. A second educational fact is that it is very difficult to change the steps of a work process/skill from the way it was initially learned. Since there is some risk of disease transmission, manikin surfaces should be cleaned and disinfected after each use. Disinfecting involves the use of a disinfectant to kill many of the microorganisms that may be on the object. Internal parts such as artificial lungs and valve mechanisms should be cleaned thoroughly between users. An equally effective and less expensive alternative to commercial disinfectants is a bleach solution. One part bleach to 100 parts water (1:100, approximately 2 cups/gallon) should be effective for training equipment, as long as the equipment is first washed with warm, soapy water and 6 American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care; Supplement to Circulation; 12(8). The major focus of infected workers providing care revolves around invasive procedures that might result in exposing the patient to the virus.

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Kuriyama S, Tomonari H, Yoshida H, Hashimoto T, Kawaguchi Y, Sakai O: Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Hayashi T, Suzuki A, Shoji T, Togawa M, Okada N, Tsubakihara Y, Imai E, Hori M: Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Cavill I: Iron status as measured by serum ferritin: the marker and its limitations. Position of the American Dietetic Association: Cost-effectiveness of medical nutrition therapy. Holland D, Lam M: Predictors of hopitalization and death amongst pre-dialysis patients: A retrospec tive study. Stenvinkel P, Heimburger O, Paultre F, Diczfalusy U, Wang T, Berglund L, Jogestrand T: Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Panichi V, Migliori M, De Pietro S: C reactive protein in patients with chronic renal diseases. Bergstrom J, Lindholm B: Malnutrition, cardiac disease, and mortality: An integrated point of view. Chauveau P, Barthe N, Rigalleau V, Ozenne S, Castaing F, Delclaux C: Outcome of nutritional status and body composition of uremic patients on a very low protein diet. Williams B, Hattersley J, Layward E, Walls J: Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Ando A, Orita Y, Nakata K, Tsubakihara Y, Takamitsu Y, Ueda N, Yanase M, Abe H: Effect of low protein diet and surplus of essential amino acids on the serum concentration and the urinary excretion of methylguanidine and guanidinosuccinic acid in chronic renal failure. Walser M, Hill S: Can renal replacement be deferred by a supplemented very low protein diet? Cupisti A, Guidi A, Giovannetti S: Nutritional state of severe chronic renal failure patients on a low protein supplemented diet. Sugimoto T, Kikkawa R, Haneda M, Shigeta Y: Effect of dietary protein restriction on proteinuria in non-insulin-dependent diabetic patients with nephropathy. Barsotti G, Ciardella F, Morelli E, Cupisti A, Mantovanelli A, Giovannetti S: Nutritional treatment of renal failure in type 1 diabetic nephropathy. Parillo M, Riccardi G, Pacioni D, Iovine C, Contaldo F, Isernia C, De Marco F, Perrotti N, Rivellese A: Metabolic consequences of feeding a high-carbohydrate, high-fiber diet to diabetic patients with chronic kidney failure. Coyne T, Olson M, Bradham K, Garcon M, Gregory P, Scherch L: Dietary satisfaction correlated with adherence in the Modification of Diet in Renal Disease Study. Coen G, Manni M, Addari O, Ballanti P, Pasquali M, Chicca S, Mazzaferro S, Mapoletano I, Napoletano I, Sardella D, Bonucci E: Metabolic acidosis and osteodystrophic bone disease in predi alysis chronic renalfailure: Effect of calcitrioltreatment. Ferreira M: Diagnosis of renal osteodystrophy: When and how to use biochemical markers and non invasive methods: When bone biopsy is needed. Hyperphosphatemia: Its consequences and treatment in patients with chronic renal disease. Llach F: Hyperphosphatemia in end-stage renal disease patients: Pathophysiological consequences. Atsumi K, Kushida K, Yamazaki K, Shimizu S, Ohmura A, Inoue T: Risk factors for vertebral fractures in renal osteodystrophy. Coco M, Rush H: Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Lau K: Phosphate excess and progressive renal failure: the precipitation-calcification hypothesis. Carlstedt F, Lind L, Wide L, Lindahl B, Hanni A, Rastad J, Ljunghall S: Serum levels of parathyroid hormone are related to the mortality and severity of illness in patients in the emergency department. Martinez I, Saracho R, Montenegro J, Llach F: the importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure. Reichel H, Deibert B, Schmidt-Gayk H, Ritz E: Calcium metabolism in early chronic renal failure: Implications for the pathogenesis of hyperparathyroidism. Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K: Bone mineral density and biochemical markersofboneturnoverinpatientswithpredialysischronicrenalfailure. TessitoreN,VenturiA,AdamiS,RoncariC,Rugiu C,CorgnatiA,BonucciE,MaschioG:Relationship between serum vitamin D metabolites and dietary intake of phosphate in patients with early renal failure. Madsen S, Olgaard K, Ladefoged J: Renal handling of phosphate in relation to serum parathyroid hormone levels. Ishimura E, Nishizawa Y, Inaba M, Matsumoto N, Emoto M, Kawagishi T, Shoji S, Okuno S, Kim M, Miki T, Morii H: Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25 hydroxyvitamin D in nondialyzed patients with chronic renal failure. Coen G, Mazzaferro S, Ballanti P, Sardella D, Chicca S, Manni M, Bonucci E, Taggi F: Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: A cross-sectional study. Madsen S, Olgaard K, Ladefoged J: Degree and course of skeletal demineralization in patients with chronic renal insufficiency. Bazzi C, Pagani C, Sorgato G, Albonico G, Fellin G, D?Amico G: Uremic polyneuropathy: A clinical and electrophysiological study in 135 short and long-term hemodialyzed patients. The relationship betweeen sensory and motor nerve conduction and kidney function, azotemia, age, sex, and clinical neuropa thy. Morena F, Aracil F, Perez R, Valderrabano F: Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal disease-related anemia. Pei Y, Cattran D, Greenwood C: Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis. Hannedouche T, Albouze G, Chauveau P, Lacour B, Jungers P: Effects of blood pressure and antihy pertensivetreatmentonprogressionofadvancedchronicrenalfailure. Ruggenenti P, Perna A, Zoccali C, Gherardi G, Benini R, Testa A, Remuzzi G: Chronic proteinuric nephropathies. Hannedouche T, Chauveau P, Kalou F, Albouze G, Lacour B, Jungers P: Factors affecting progression in advanced chronic renal failure. Nakano S, Ogihara M, Tamura C, Kitazawa M, Nishizawa M, Kigoshi T, Uchida K: Reversed circadian blood pressure rhythm independently predicts endstage renal failure in non-insulin-depen dent diabetes mellitus subjects. Toth T, Takebayashi S: Factors contributing to the outcome in 100 adult patients with idiopathic membranous glomerulonephritis. Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R: Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Locatelli F, Alberti D, Graziani G, Buccianti G, Redaelli B, Giangrande A: Prospective, randomised, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency. Standards of Medical Care for Patients with Diabetes Mellitus, Position Statement. The Diabetes Control and Complications Trial Research Group: the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabe tes mellitus. Microalbuminuria Collaborative Study Group, United Kingdom: Intensive therapy and progression to clinical albuminuria in patients with insulin dependent diabetes mellitus and microalbuminuria. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: A randomized prospective 6-year study. National High Blood Pressure Education Program Working Group on Hypertension Control in Chil dren and Adolescents: Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A working group report from the National High Blood Pressure Education Program. Randomised trial of old and new antihypertensive drugs in elderly patients: Cardiovascular Mortality and Mrobidity in the Swedish Trial in Old Patients with Hypertension-2 Study. Ruggenenti P, Remuzzi G: Angiotensin-converting enzyme inhibitor therapy for nondiabetic progres sive renal diseas. Effects of losartan on renal and cardio vascular outcomes in patients with type 2 diabetes and nephropathy. Yusuf S, Sleigh P, Pogue J, Bosch J, Davies R, Dagenais G: Effects of an angiotensin-converting enzymeinhibitor,ramipril,oncardiovasculareventsinhigh-riskpatients. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial. Manttari M, Tiula E, Alikoski T, Manninen V: Effects of hypertension and dyslipidemia on the decline? Tonolo G, Ciccarese M, Brizzi P, Puddu L, Secchi G, Calvia P: Reduction of albumin excretion rate in normotensive microalbumiuric type 2 diabetic pateints during long-term simvastatin treatment. Buemi M, Allegra A, Corica F, Aloisi C, Giacobbe M, Pettinato G: Effect of fluvastatin on proteinuria in patients with immunoglobulin A nephropathy. Albertazzi A, Di Liberato L, Daniele F, Battistel V, Colombi L: Efficacy and tolerability of recombinant humanerythropoietintreatmentinpre-dialysispatients:Resultsofamulticenterstudy.

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Collaborative Group 2001), indicating that these treatment the drug versus placebo trials achieved the greatest reduc effects are independent. This finding is plausible, because they tions in blood pressure, and a dose-response relationship was act through different mechanisms and because observational apparent between blood pressure reduction and reduced risk of studies do not suggest a large interaction (Neaton and stroke. This finding is con achievedsurprisinglyrapidly:formostoutcomes,riskappearsto sistent with the size of associations observed in cohort studies. Clear evidence indicates that all the major drug classes have Forexample,individualswithcholesterolloweredinthepasttwo similar effects on the risk of stroke and coronary heart disease or more years are at approximately the same coronary heart dis per mmHg reduction in blood pressure (Blood Pressure ease risk as otherwise identical individuals whose cholesterol has Lowering Treatment Trialists? Collaboration 2003; Lawes and been at that level for decades (Law,Wald, and Thompson 1994). The only clear evidence of clinically important, Pharmacological agents for weight loss that have been sub class-specific effects are with agents that block the renin ject to randomized controlled trials include dexfenfluramine, angiotensin system, which reduce diabetes incidence by about sibutramine, orlistat, and phentermine/fenfluramine (although one-quarter, and with calcium channel blockers, which reduce the last has been withdrawn because of a reported association heart failure less than other agents (although this result may be between the drugs and valvular heart disease). Overall, trials partly caused by misclassification, because a known side effect suggest only modest weight-loss effects, with an average net of calcium channel blockers is ankle edema, which is a diag weight loss of 1. Results of more drugs should be provided and how long-term adherence a systematic review of trials assessing sibutramine were similar can be maximized. Weight loss resulting from gastric bypass dietary interventions, but also some other interventions such as varied from 50 to 100 kg six months to a year following surgery resins and niacin). A good correlation has been found 23 to 37 kg more weight loss than conventional treatment and between reduction in total cholesterol and relative risk reduc that this loss was maintained for eight years (Clegg and others tion. Furthermore, gastric bypass surgery appears to be more pressure lowering, that even though some drugs are more beneficial than gastroplasty or jejunoileal bypass. Where possible, this chapter deals with the separate perceived), and the costs of treatment. First, the costs for identify Health providers may use multiple strategies to increase ing those requiring treatment vary significantly by level of eco compliance and adherence. Patient-centered interventions nomic development and by urban versus rural location. Second, in some countries, such as India, dosing schedules; providing drug information leaflets, medica that are large producers of generic drugs, prices are reported to tion charts, and special reminder packaging for medications; be lower than in most other drug-producing or -importing holding group sessions for education and family-oriented dis countries. Third, this approach allows researchers and policy ease management therapies; and implementing automated makers to understand the constituent costs so that they can telephone assessment and self-care education calls with nurse examine where cost reductions may be most beneficial. Ultimately, the net effect is reflected Several trials and overviews have attempted to assess the in cost-effectiveness analyses. Unless otherwise stated, costs are value of different interventions to improve compliance and in 2001 U. Annual drug costs for medications to assessment of the separate effects of the intervention compo lower blood pressure and cholesterol vary widely by country nents. Haynes and others? (2003) systematic review concludes and depend on whether generics are available and used. For that, overall, no single approach to improving adherence can be example, according to the International Drug Price Indicator recommended. Because and counseling, easier access to care, reminders, close follow drug costs vary by up to two orders of magnitude across coun up, supervised self-monitoring, family therapy, and rewards for tries, results of cost-effectiveness analyses are particularly success can improve adherence and treatment outcomes in sensitive to their input prices. The costs of these medications have dropped did not lead to large improvements in adherence or treatment considerably in recent years, and now the annual costs for outcomes and were relatively resource intensive. Statins will become increasingly dose combination treatment or unit-of-use packaging. A basic life year saved, depending on the percentage reduction in cho metabolic panel for those on diuretics or for measuring renal lesterol (1 to 4 percent). The two ratios, depending on underlying risk, age, and costs of medica most important aspects of the cost-effectiveness of any primary tions. For example, a commu is likely to differ considerably now that statins are off patent. Costs include both program-level costs life year saved in the Air Force/Texas Coronary Atherosclerosis (media, training, and administration) and patient-level costs Prevention Study cohort with average cholesterol levels was (medicines, health care visits, diagnostic tests). Ingeneral,youngerandolderagegroups based on a standard ingredients approach and on regional esti tend to have the least favorable cost-effectiveness ratios. The incremental risk and the many years of treatment required before realizing a cost-effectiveness ratios for the strategy assessing absolute risk benefit. These estimates are in Personal Interventions to Lower Blood Pressure or international or purchasing-power parity dollars (see chapter 15 Cholesterol in Developing Countries for an explanation). The nonpersonal interven we have derived assessments of cost-effectiveness by extrapo tions, including efforts to reduce salt intake in processed foods, lating from results in developed countries presented earlier. Personal Goldman and others (1991) report that a decline in the cost of interventions based on treatment guidelines were cost lovastatin by 40 percent, once generic, would result in a roughly effective; however, when the strategies for treating high choles 30 percent reduction in the cost-effectiveness ratio. However, terol or hypertension were compared with the absolute-risk this finding does not take into account that both the underly approach, they were not favorable and were dominated by the ing epidemiology and the costs can be quite different across latter, meaning that the absolute-risk approach of treating those and within countries and regions. For sonal health service interventions or combinations of interven an example of a country-specific analysis, see box 45. This suggestion is especially relevant for intake,improve blood pressure generally,and reduce cholesterol developing countries, given that suitable components are all and obesity levels. Good evidence indicates that single-pill combi ment with statins of those above two different cholesterol-level nations increase adherence to drug regimens (Connor, Rafter, thresholds (greater than 6. We treatment with beta-blockers and diuretics of those above two used a Markov model to evaluate the cost-effectiveness of such different hypertension thresholds (greater than 160 mmHg or a hypothetical pill or combination packaging of the individual greater than 140 mmHg), and treatment of individuals with medications. We modeled the effect of a pill that included half 860 | Disease Control Priorities in Developing Countries | Anthony Rodgers, Carlene M. Costs of prevention and nondrug costs for treatment according to absolute risk are converted at an estimated regional average ratio of exchange rate to purchasing-power parity rate; drug costs are not converted, assuming drugs to be imported at world prices. The share of drug costs in total treatment cost, as a function of risk, is taken from the estimates for India in table 45. Dominated strategies were both less effective and more costly than comparator strategies. We applied the model to a population countries, the relative differences between the different groups of 1 million adults over the age of 35, with the costs and bene receiving the ?polypill?compared with the groups not receiving the Growing Burden of Risk from High Blood Pressure, Cholesterol, and Bodyweight | 861 Box 45. Data on diabetes prevalence effectiveness ratios were quite sensitive to the costs of were included to further refine risk estimates. The four absolute-risk number of life years gained compared with the no pri strategies had the four lowest incremental cost-effectiveness mary prevention strategy and is therefore cost saving. A dominated strategy is one that is both more expensive and less effective than the preceding strategy to which it is compared. Note: the regimen includes aspirin, a beta-blocker, a thiazide diuretic, an angiotensin-converting enzyme inhibitor, and a statin. Because access to cardiovascular health care in develop Interventions to Reduce Bodyweight ing countries often depends on patients? ability to pay, the poor No large-scale randomized trials of weight reduction as an iso would stand to benefit the most from a low-cost intervention lated intervention are available on which to base estimates of such as a polypill. Thus, costs per life year saved would have to be developing countries; however, in many developing coun modeled to project benefits. One barrier to In the cost-effectiveness analyses, most of the gains are reported adopting preventive therapy based on absolute risk has in cost savings either from particular interventions, such as been its relative complexity compared with dichotomous decreased hospitalizations resulting from the improved combi diagnosis-based strategies, such as hypertension?no nation therapy of the polypill, or from a more efficient means hypertension. Those chronic these methods would likely involve low-cost algorithms diseases can result in significant impairments, thereby prevent completed by a multipurpose health care worker involv ing those affected from continuing to work and sometimes also ing,for example,the collection of data on age,sex,tobacco requiring the services of other family members, who them use, blood pressure, waist circumference, and urine selves end up having to leave the workforce. The development of different levels of resulting from disability include the loss of wages for major screening protocol may also be needed in certain settings. Leeder and others (2004) estimate and cardiovascular profiles in developing countries. This strategy could (defined as those years between the ages of 35 and 64) will mean developing an index of healthy life years at risk nearly double by 2030. Those later adult working years are par from a cardiovascular event in the next five years, which ticularly important, given the many years of investment in skills would require taking case fatalities into consideration through formal education and experience that would be lost. Many of the combina different patient groups and populations at different tion cardiovascular preventive approaches outlined in this stages of the health transition. Measure the potential costs and benefits of adding other able departure from existing paradigms, such as hypertension active agents, such as vitamins or diabetic medications. Quantify the extent of improved access, acceptability, several areas to develop, implement, and evaluate this strategy. Cardiovascular Events: Results of Prospectively Designed Overviews of Support demonstration projects to determine the limita Randomised Trials: Blood Pressure Lowering Treatment Trialists? The analyses presented in this chapter indicate that providing ?The West of Scotland Coronary Prevention Study: Economic Benefit Analysis of Primary Prevention with Pravastatin. Preventing and Disease Death in Presence of Myocardial Infarction: the Framingham Study. Comparative Quantification of Health Risks: Global and Regional Heart Protection Study Collaborative Group.

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Some samples can be stabilized by refrigeration, some may require freezing, others may need protection from light, and still others might require analysis within limited timeframes. If a blood sample is not immediately placed on ice, the continued formation of ammonia during transport may cause falsely high results suggesting liver disease when no disease is present. Glucose, on the other hand, is consumed by blood cells when a sample of whole blood is stored at room temperature. Signifcant amounts of glucose can disappear in a matter of 30?60 minutes, risking a failure to recognize high glucose or to falsely identify someone as havingFigure 5-1. Sometimes it is not discovered that an assay is out of control until after patient samples have been analyzed. If the method fails to meet performance standards (?out of control?), the results from testing patient samples will be erroneous. In this case, the cause of the problem must be identifed and corrected and then the patient samples retested. Part of the evaluation of test method accuracy includes evaluation of the efect of potential interferents. The indices representing these conditions are abbreviated by the letters H, I and L. Hemolysis results in the sample appearing red; icterus as yellow to brown; and lipemia results in a milky or turbid appearance. Qualitative visual scales, ranging from 1+ to 4+, indicate the relative degree of each of these conditions. E ect of the Presence of H, I or L the color or turbidity of the interferent can alter the readings taken by a spectrophotometer so the absorbance signal does not refect the true concentration of analyte. By taking absorbance measurements at the seven photometric measurements of absorbance at several diferent wavelengths. A mathematical algorithm can designated wavelengths, the concentrations of each of these then be used to compute the relative amount of each interferent and provide a semiquantitative estimate. This estimate can be made during the background reading time, before any active reagents are added, or as a separate test. For example, if the test for potassium has been found to be elevated when H > 2+, but not when L or I are elevated, the laboratory may decide not to report potassium results if H > 2+, or it may choose to report the result with a conditional statement indicating the result is likely to be overestimated because of the high H index. The presence of these antibodies (called heterophile antibodies) can lead to a falsely high or falsely low result. Patients may develop heterophile antibodies if they receive immunotherapies, a vaccine containing serum from another species, or even through environmental exposure. If a provider questions the result, it is possible to repeat the test adding an anti-heterophile antibody or a blocking substance that will bind to the heterophile antibody in the sample before analysis. The anti-heterophile antibody or blocking substance binds to the heterophile antibody in the patient sample and prevents it from interfering in the test. Some immunoassays include anti-heterophile antibodies or blocking agents in the reagents for the test, to reduce the possibility of interferences from heterophile antibodies in the patient sample. This approach is acceptable when only knowing that a result is elevated is sufcient for medical management. In such cases the usual approach is to dilute the sample and reanalyze a diluted aliquot of the sample, mathematically correcting the measured result by a dilution factor. For example, if the original sample is diluted by taking 1 mL of sample and adding 9 mL of an appropriate diluent (a term for the solution used for making dilutions), the measured result in the diluted sample will be multiplied by 10 to give the value for the original sample. Manual dilution and reanalysis steps are often undesirable because they are subject to human error such as mismeasurement, miscalculation and use of the wrong diluent. Some tests are sensitive to the diluent so the proper diluent and water, saline or even the zero calibrator may be required for specifc tests. Manual dilution and reanalysis can also introduce inefciencies such as delayed reporting of results and delays to other sample testing. Automated chemistry analyzers often include automatic dilution for determining the concentrations of out-of-range samples without human intervention. If the diluted sample gives a result that is in range, the instrument performs a calculation to correct the reported result with the dilution factor. While this process takes additional time for the dilution and reanalysis, it ofers the advantage of minimizing errors and promptly addressing the issue and providing a quantitative result for the sample within minutes. Two diferent read windows, the routine reaction read window and an earlier read window, may be monitored to observe the reaction rate. If the sample has a high concentration of analyte, the added enzymatic substrate reagent is quickly consumed, resulting in substrate depletion. The reaction no longer refects the true enzyme quantity or activity and cannot be measured. The result is reported as greater than linearity (too high to measure) or in some cases, if substrate depletion is not detected, as a falsely low result. This illustration explains the use of two read windows, a main or routine read window, and an earlier read window, to accurately determine the enzyme activity. For example, if less than three linear data points fall within the main read window, the system will use the earlier read window to calculate the result. FlexRate Extends Linearity of Enzymes By read window can use an algorithm to calculate the concentration of enzyme activity while the reaction is stillUsing 2 Absorbance Read Time Windows in the linear range. Early Rate Read Time Main Read Time 1 1 = Low Enzymatic Activity 3 2 2 = Medium Enzymatic Activity 3 = High Enzymatic Activity Photometric Reads Figure 5-4: Use of alternate read windows to extend linearity of enzymes FlexRate Description: 1. If the values are nonlinear, then FlexRate uses the absorbance from an earlier read (Flex) window to calculate the patient result. Examples of random errors include air bubbles or particulate matter in the sample resulting in pipetting a too small volume of sample. Fortunately, many automated analyzers are programmed to recognize the presence of bubbles, microclots, low sample volume or other random errors. Random Error From Bubbles, Foam or Precipitates for analysis can sense when the sample is not fowing at the expected rate, as it might be if impaired by the presence of a microclot, and generate a pressure monitoring error for the analysis. Instruments can recognize if the absorbance signal is not demonstrating the expected steady increase or decrease during the reaction time and is instead showing some random high or low values, as would be seen with a bubble or particle foating through the light path. When bubbles or clots or other random events lead to unexpected sampling or signal patterns, the instrument can alert the operator that this test result is suspect and needs to be retested. Panel A Panel B Read Read Window Window Time Time Expected absorbance increases are smooth, regular curves (Panel A). The presence of bubbles, foam or particle in the photometric window will cause sporadic high or low values (Panel B). A Test method incorrectly calibrated B Collection of blood in wrong kind of tube C Presence of interfering substance in specimen D Delay in sending the report to the provider 2. Which type of analytical error can be prevented by a good quality control program? A Instrument not properly calibrated B Presence of interfering substances in sample C Presence of bubbles in the light path of a photometric method D Analyte concentration so high it depletes the active reagent 3. A Instrument not properly calibrated B Presence of interfering substances in sample C Presence of bubbles in the light path of a photometric method D Analyte concentration so high it depletes the active reagent 4. What option(s) might be employed if a test result is above the upper limit of the test measurement range? Clinical chemistry tests measure a wide variety of analytes that refect many diferent organ systems and diseases. Some test results are specifc indicators for a single organ system or disease; others are general indicators of a disease or disorder, but do not pinpoint the specifc organ or disease process. Some tests help diagnose a disease, others monitor the course of the disease progression or efectiveness of therapy, and still others are used to screen for risk of developing a disease. This section gives only a sampling of some of the more common analytes that are measured in the clinical laboratory. These range from ions to small molecules to proteins (macromolecules) to lipids and lipoproteins that circulate in complexes containing hundreds of molecules and macromolecules. Reference ranges or expected results for healthy adult individuals are provided as a guide for discussion in this chapter. These values were sourced from the 5th edition of Tietz Fundamentals of Clinical Chemistry unless otherwise stated. These values may difer with diferent patient populations, regions of the world and assay methodologies, and should be verifed by laboratories prior to use.

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Replacement of salamon with shotor diluent and egg yolk with low density lipoprotein for chilled storage of ram semen. Chilled storage of ram semen improves with the addition of egg yolk and glycerol to milk? An overview of the impact of the high variation in the ovarian reserve on ovarian function and fertility, utility of anti-Mullerian hormone as a diagnostic marker for fertility and causes of variation in the ovarian reserve in cattle. Antral follicle count reliably predicts number of morphologically healthy oocytes and follicles in ovaries of young adult cattle. The anatomy of the sheep cervix and its influence on the transcervical passage of an inseminating pipette into the uterine lumen. Anti-Mullerian hormone plasma concentration in prepubertal ewe lambs as a predictor of their fertility at a young age. Effects of epinephrine and hypotaurine on in-vitro fertilization in the golden hamster. Survival and fertility of ram spermatozoa frozen in pellets, straws and minitubes. Taurine and hypotaurine: their effects on motility, capacitation and the acrosome reaction of hamster sperm in vitro and their presence in sperm and reproductive tract fluids of several mammals. The effect of season on the scrotal circumference and sperm motility and morphology in rams. Expression of the mouse anti-Mullerian hormone gene suggests a role in both male and female sexual differentiation. Effect of cervical and vaginal insemination with liquid semen stored at room temperature on fertility of goats. Effect of deposition site and sperm number on the fertility of sheep inseminated with liquid semen. Effect on field fertility of addition of gelatine, different dilution rates and storage times of cooled ram semen after vaginal insemination. Effect of different levels of egg yolk on ram sperm coating and preserving at 5? C. Anti-mullerian hormone at weaning and breeding as a predictor of beef heifer fertility. Effect of composition of Tris-based diluent and of thawing solution on survival of ram spermatozoa frozen by the pellet method. Preservation of bovine spermatozoa in yolk-citrate diluent and field results from its use. Effect of solid storage at 5? C on sperm motility of goat semen by addition of gelatin. Regulation and role of anti-Mullerian hormone in bovine reproduction (Doctoral dissertation). Relationship between total spermatozoa per insemination and fertility of bovine semen stored in Caprogen at ambient temperature. In vitro evaluation of ram sperm frozen with glycerol, ethylene glycol or acetamide. The effect of penicillamine, hypotaurine, epinephrine and sodium metabisulfite, on bovine in vitro fertilization. Effects of five cryoprotective agents on quality of sheep epididymal spermatozoa during pre-freezing. Production of anti-Mullerian hormone: another homology between sertoli and granulosa cells. Recent developments and concepts in the cryopreservation of spermatozoa and the assessment of their post-thawing function. Anti-Mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Lipids and calcium uptake of sperm in relation to cold shock and preservation: a review. Sire breed differences in pregnancy rate of hair sheep ewes following liquid semen vaginal artificial insemination. Use of liquid semen artificial insemination in Katahdin sheep in a commercial farm setting. Semen storage at 23, 4 or-196? C and its application to artificial insemination in small-tail Han sheep. Use of image analysis to assess the plasma membrane integrity of ram spermatozoa in different diluents. Variables in the model included extenders, temperature, hours (repeated measures) and interactions. Most of the sperm motility parameters were higher after storage at 4? C compared with 15? C. Within 24 h, percentage of progressive motile sperm decreased sharply 34 regardless of extenders or storage temperatures. Progressive motility of spermatozoa is positively correlated to fertilizing capacity. Fresh diluted and chilled ram semen is an alternative to frozen storage (Salamon and Maxwell, 1995). Better motility of ram semen was found after storage at 4? C for 2 to 3 d compared with frozen storage for several weeks (Wusiman et al. Differences in motility among experiments may be due to the type of extender and storage duration. Animal management Five mature Katahdin rams were clinically healthy and raised on mixed tall fescue (Schedonorus arundinacea) and bermudagrass (Cynodon dactylon) pasture. Semen was collected by electroejaculation into 15 ml polystyrene tubes, screw capped and placed immediately into a thermo-flask (Lab-line Instruments Inc. Sperm motility parameters were analyzed using the default analysis settings recommended by manufacturer for ram semen. At least four fields were scanned, with 30 video frames captured per field at a frame rate of 60 Hz. Preparation of semen extenders Milk extender All the ingredients were from Sigma Company unless otherwise mentioned. On the day of semen collection, egg yolk was added to 95 ml of the stock solution as described for milk extender. Preparation of semen for storage Semen was initially extended to 150 million cells/0. Half of the straws were placed in water in a laboratory flask (Sigma Chemical Co, St. Minimum and maximum static size and intensity gates were used to eliminate the chance of counting any other cells. The illumination intensity for fluorescent illumination was set up between 2050 and 4050. The chilled extended semen was pre-warmed in a thaw jug maintained at 35? C for 15 sec. For semen samples diluted using milk extender, 10 ?l of Hoechst 33342 stain was added. Statistical analysis Semen motility parameters were analyzed at 24, 48 and 72 h after storage. Variables in the model included extender, temperature, hour (as a repeated measures of 24, 48, and 72 h), and all 2 and 3 way interactions. Discussion Effective technologies are needed to move sheep germplasm readily between farms to facilitate genetic improvement and to allow the use of superior genetic resources. Artificial insemination enables fast spread of quality genetic traits between farms. Artificial insemination with frozen ram semen results in low conception rates (20-30%; Salamon and Maxwell, 1995). Fresh diluted and cold stored semen is an alternative to frozen storage (Salamon and Maxwell, 1995). Ram semen stored at 4? C for a short period (2 to 3 d) of time was more beneficial than frozen storage for a long-period of time (-196? C for several weeks; Wusiman et al.

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In monkeys, radiothyroidectomy perform A number of clinical or ed at mid-gestation (80 days) induced a great experimental observations underline the of slight but significant decrease in fetal importance thyroid function in the of body weight (= 10%), measured 70 days later regulation growth. Similarly, in the fetal lamb, a thyroid hormone deficiency, linked to poor maternal iodine intake, was associated Dwarfism resulting from congenital with a 20% reduction in the birthweight hypothyroidism (Setchell et al. The only exception could be retardation, growth could be reversed the human newborn in whom it is general deficiency easily by thyroxine administration ly assumed that moderate congenital (Utiger, 1979). In small mammals, which In species with low maturity at birth, the are less mature at birth, this influence fetal growth is apparently independent of seems to appear only after birth when thyroid function, as in the rabbit (Jost et thyroid function is well developed (this al. As pituitary function is significantly attention on two aspects of thyroid impaired in dwarf mice, these data are in hormone activity, the influence on growth agreement with the results published by factor production and the relationship to Scanes et al. The mandillary gland (Aloe & Levy-Montaicini, administration of T3, three times a week, 1980; Lakshmanan et al. The same data have submandillary gland (Fisher Gresik et 1981; Hosai et been reported in rats developing a 1982; aL, aL, 1981; Walker et al. In these cells, production growth in tumor this with an it has been shown that physiological pituitary cells; factor, amounts of T3 (= 2. Moreover, the T3 influences growth hormone and stimulation of gene transcription is dose somatomedin production, and also dependent and occurs without a latency their tissue activities period (Yaffe & Samuels, 1984). This it is well-established that T3 discrepancy needs further clarification in Today influences and secretion of the species studied. Therefore, this aspect of thyroid hormone In this paper, we have shown that the so action needs clarification. Moreover, it appears that its T3 increases somatomedin production somatic effects are on strongly dependent thyroid status and particularly on T3 Whatever the mechanisms T3 production. On the other hand, only specific effects, but also as a in chickens, Decuyp6re et al. In vitro, Binoux et aL (1985) been performed in order to stimulate observed that T3 stimulates insulin-like growth performance in domestic animals. Taking into account all hormone excess is as unfavourable as these results, it appears that T3 could thyroid hormone deficiency, and that it is increase autocrine or paracrine, as today very difficult to induce slight endocrine stimulation of growth by modifications in T3 production. The half-life (1970) the plasma growth hormone concen of these enzymes is short (about 30 min tration in the fetal lamb. Metabolism 30, 1086-1090 the identification of a factor inducing a Bhakthavathsalan A. Therapeutic Agents Produced by Genetic (1988) Nucleotide sequence of rat liver iodothy Engineering. Metabolism 28, for in the rat : a dependence growth study 291-299 fetal, neonatal and involving transplanted Burstein P. Effect of Huybrechts (1987) growth hormone-dependent somatomedin, or status of broilers on insulin-like factor and its carrier hyper hypothyroid growth protein growth, adiposity and levels of growth in rats. Growth 50, growth hormone gene mediates regulated 325-339 expression by thyroid hormone. Alterations in monodeio thyroid hormone metabolism in maternal and Chopra (1980) dination of in the rat : fetal sheep. In : the Physiolo In : Therapeutic Agents Produced by Genetic gical Development of the Fetus and Newborn Engineering. Plasma somato Kavanaugh (1987) during growth of normal and dwarf pullets and response to exogenous growth hor trophin cockerels. Endocrinology concentrations of somatomedin-C in hypophy 103, 1453-1457 sectomized, dwarf and intact growing domestic Klein A. Growth 50, 12-31 pituitary growth hormone content in rats treated neonatally with high doses of 1-thyroxine. Endocrinology 109, regulation of the growth hormone gene : 582-587 of the rate of to the relationship transcription Walker P. Background the clinical manifestations of thyrotoxicosis (hyperthyroidism) or hypothyroidism may be so non? Guidelines, of course, cannot apply to every clinical situation, nor can they serve as a substitute for sound clinical judgement. Indications for Screening Patients with thyroid enlargement and/or signs and symptoms suggestive of thyroid disease should be tested to assess thyroid function. While screening of the general population for thyroid dysfunction is not recommended, there are certain high risk groups that clearly benefit from screening. These include: All newborns (neonatal screening) Women over 50 years of age Women trying to conceive Pregnant women during the first trimester Women 6 weeks to 6 months postpartum (this is a period of high risk for thyroid disease) Patients on medications known to cause thyroid dysfunction (see section 6) Individuals with a family history of thyroid disease or autoimmune disorders Patients with hyperlipidemia, hypertension, diabetes mellitus 3. Therefore, efficacy of treatment is best monitored by testing fT3 and fT4 every 4 to 6 weeks. For the purpose of diagnosis, secondary hypothyroidism is almost always associated with other clinical and laboratory evidence of pituitary dysfunction. Laboratory documentation of secondary hypothyroidism will depend on a reduced serum fT4 level and associated clinical evidence. Ontario community laboratories have elected to continue to report the higher upper limit of normal (4. The reader is advised to consult a specialist for interpretation in the presence of these agents. Users must ensure that their own practices comply with all specific legislative, government policies or accreditation requirements that apply to their organizations. Given the complexity of legal requirements, users are reminded that whenever there is uncertainty regarding whether some aspect of a Guideline is appropriate for their practice or organization, further direction should be obtained from the Laboratory Director, their own professional association, college and/ or legal counsel or appropriate government ministry. Transient hypothyroidism: Iodine deficiency Iodine excess Infants with passive transfer of maternal thyrotropin receptor blocking antibodies 4. References Introduction: Thyroid hormones are essential for the normal development of the brain. Thyroid disorders in the newborn form a complex group of conditions, many of which are the focus of active research at present. Well established screening programmes have been implemented to detect congenital hypothyroidism, which is associated with mental and growth retardation if left undetected and untreated. Thyroid status in the newborn is also influenced by maternal thyroid disease, with maternal thyroid disease associated with adverse pregnancy outcomes including neonatal encephalopathy [1, 2], and infants of mothers with Graves disease at risk of neonatal thyrotoxicosis. Iodine deficiency impacts on many populations to result in transient neonatal hypothyroidism and goitre, with potentially negative effects on infant and child development [3, 4]. Iodine excess may result from use of iodine containing antiseptics to mother or infant, radiology contrast agents for line insertion and amiodorone in mother or infant. Iodine excess has been associated with transient hypothyroidism especially in preterm infants [5-7], although its longer term effects are unknown. Transient hypothyroxinemia in preterm infants has been reported to be associated with adverse developmental outcomes [8-12]. However, there is no consensus on definition of hypothyroxinemia, and trials of treatment of preterm infants at risk of transient hypothyroxinemia are yet to demonstrate a benefit [13-15]. As transient hypothyroxinemia is associated with illness severity in preterm infants [16], it may be that the association with abnormal developmental outcome is due to these factors and not the thyroid response. This guideline provides a pragmatic, evidence based approach to dealing with thyroid disorders in the newborn infant. Congenital hypothyroidism Deficiency of thyroid hormone may result in mental and growth retardation if congenital hypothyroidism is not diagnosed and treated adequately early in life [17, 18]. Most infants will still appear clinically normal before 3 months of age, by which time some brain damage has usually occurred. Symptoms or signs, when present, may include prolonged neonatal jaundice, constipation, lethargy and poor muscle tone, poor feeding, a large tongue, coarse facies, wide fontanelle, distended abdomen and umbilical hernia. Incidence and risk factors: the incidence of primary congenital hypothyroidism was reported as 1:3,541 in Victoria between 1977-88 [20], and 1:2824 in Western Australia between 1988-98 [21]. Common causes of primary congenital hypothyroidism include [20]: Dysgenesis (various abnormalities in the formation of the thyroid gland). Examine for clinical features including coarse facial features, large tongue, umbilical hernia, constipation, poor feeding, intellectual and developmental delay, goitre, jaundice, growth parameters and other congenital problems (eg heart disease). Screening before 48 hours produces a high rate of false positive results due to this surge.

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Some examples of ambiguity are: client doubts that the medication will actually work; they are unclear about what to do; or if they doubt they have the necessary skills. One needs to evaluate that the client has understood the information, knows how to use it, and has a feeling of self-efficacy or confidence in their ability to do what is needed. Then, nurses elicit information again to check for concerns or questions resulting from the new information. Motivational interviewing uses five principles or counseling techniques to assess and create motivation within the client (Berger, 2004a,b; Miller & Rollnick, 1991; Smith, Heckemeyer, Kraft & Mason, 1997). Express empathy Empathy is defined as the ?ability of the provider to accurately reflect what the client is saying? (Moyers, 2000; p. Instead of creating defensiveness by asking, ?Can?t you think of something else to relax you? Avoid arguments By avoiding arguments, the client is more likely to see the healthcare provider as being on his/her side. For example, the client may say that he or she enjoys going to the bar and drinking with his or her friends for most of the weekend, and how he or she hates taking medication especially those that do not make him or her feel well. In the next sentence, he or she may add that since he or she was diagnosed as having high blood pressure, he or she is very worried about having a stroke. Ask the client about the pros and cons of the changes that are needed and then listen carefully for discrepancies that allow for the creation of dissonance. For example, say, ?What do you want to happen as a result of taking this medicine for your blood pressure? For example, the client says, ?Look, I haven?t had any real problems with my smoking so far, so don?t worry about it. It is important to notice not only actual changes in behaviour, but also contemplated changes, expressed in a positive manner. Asking open-ended questions sets the stage for reflective listening, affirmations and summation. Reflective listening: As a foundational skill in motivational interviewing, reflective listening is useful to address resistance. Reflections can be simple ?you?re feeling sad? to more complex, ?It sounds like you are concerned what smoking all these years may have done to your overall health. Nurse (simple reflection): You are having a hard time understanding why we need to do this, aren?t you? The nurse has rolled with resistance and let the client know that her concerns have been heard. I know that I should take my blood pressure medication so that I do not have a stroke or other problems but it is really difficult for me to get to the pharmacy as I don?t drive and at times, I just don?t have enough money to pay for the pills. Resistance is information and reflection is useful to explore where the resistance is coming from and why it is there. Praising or complimenting and exploring past successes help to build a therapeutic relationship. For example, ?With all of the problems that you have been having lately Jane, I really appreciate that you were able to come to the appointment today. Summarizing or reframing: Reframing pulls the information together so that the client can reflect upon it. Nurse: Jane, I understand how hard it must be to get to the pharmacy when you do not have a car. You have mentioned to me how proud you are to be 84 years old and still be living independently and I must admit that this is a wonderful quality. I know, from our many conversations, that you understand how important it is to keep your blood pressure under good control. The summary links together the main points of the interview, both past and present. The ambivalence is clear and the reflection in the end encourages the client to address the ambivalence (whether to continue to struggle to get her prescriptions filled or ask someone to help). Personalized feedback: this can be done on a one-to-one basis or through the use of standardized tools; for example, a chart showing the change of blood pressure toward the target levels as the client adheres to the goals set at a previous visit. Taking your blood pressure at home: Preparing to take your blood pressure: Read the instructions that come with your monitor carefully. Have your blood pressure checked using both your home monitor and the clinic equipment. The number of daily servings in a food group may vary from those listed, depending on calorie needs (see chart below). For example, 1 tbsp of regular salad dressing equals 1 serving; 1 tbsp of a lowfat dressing equals? Choose lowfat (1 percent) or fat free (skim) dairy products to reduce your intake of saturated fat, total fat, cholesterol and calories. Because the plan is high in fibre, it can cause bloating and diarrhea in some persons. To avoid these problems, gradually increase your intake of fruit, vegetables and whole grain foods. Use fruits or other foods low in saturated fat, cholesterol and calories as desserts and snacks. Food Groups Sodium (mg) Grains and grain products Cooked cereal, rice, pasta, unsalted,? In cooking and at the table, flavour foods with herbs, spices, lemon, lime, vinegar, or salt-free seasoning blends. Cut back on instant or flavoured rice, pasta, and cereal mixes, which usually have added salt. One important note: If you take medication to control high blood pressure, you should not stop using it. The system is for use with adults age 18 years and over, with the exception of pregnant and lactating women. Excess fat around the waist and upper body (also described as an ?apple? body shape) is associated with greater health risk than fat located more in the hip and thigh area (described as a ?pear? body shape). The cut-off points are approximate, so a waist circumference just below these values should also be taken seriously. In general, the risk of developing health problems increases as waist circumference increases above the cut-off points listed above. To determine waist circumference, the individual taking the measurement should stand beside the individual. Additional details regarding waist circumference can be found at Health Canada: How often during the last year have you found have on a typical day when you are drinking? Never (0) Never (0) Less than monthly (1) Less than monthly (1) Monthly (2) Monthly (2) Weekly (3) Weekly (3) Daily or almost daily (4) Daily or almost daily (4) 6. Have you or someone else been injured as a a first drink in the morning to get yourself going result of your drinking? How often during the last year have you had a No (0) feeling of guilt or remorse after drinking? The following self-administered questionnaire is designed to help individuals discover their vulnerability quotient and to pinpoint trouble spots. Be sure to mark each item, even if it does not apply for example, if you don?t smoke, circle 1 next to item six. A score over 30 indicates some vulnerability to stress; you are seriously vulnerable if your score is over 50. You can make yourself less vulnerable by reviewing the items on which you scored three or higher and trying to modify them. Concentrate first on those that are easiest to change for example, eating a hot, balanced meal daily and having fun at least once a week before tackling those that seem difficult. The Toolkit is recommended for guiding the implementation of any clinical practice guideline in a healthcare organization. The Toolkit provides step-by-step directions to individuals and groups involved in planning, coordinating, and facilitating the guideline implementation. Specifically, the Toolkit addresses the following key steps in implementing a guideline: 1. This list was com piled based on existing knowledge of Review Process Flow Chart evidence-based practice websites and recommendations from the literature. Review of original 2005 guideline based on new evidence Literature Review Concurrent with the review of existing guidelines, a search for recent literature Supplement published relevant to the scope of the guideline was conducted with guidance from the Team Leader.

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The progress of this strategy was interrupted by a simulated cabin crew request to clarify the violent vibration felt within the cabin. The captain immediately invited the cabin crew member into the flight deck and was prepared to give a brief covering the nature of the emergency, his intentions, and the time remaining before the landing and if there were to be any special instructions. Fortunately before being completely distracted by this interruption the captain was able to refocus on the engine failure and associated priorities. The remainder of the simulator detail was handled well by the crew with some commendable management. If not, then it could be that the debrief assisted the crew in confirming their actions for future similar events. An individual should not normally fail a skill test or proficiency check for poor non-technical skills in isolation; the failure should normally be linked to a technical failure. Maintaining and/or not exceeding important parameters such as airspeed and altitude became the norm early on, and are still used today along with many other indicators such as good navigation and the ability to consistently demonstrate certain manoeuvres such as take off and landing. Such measures are relatively objective, meaning that the opinion of the assessor should have only a small overall effect. However such indicators give little insight into the non-technical performance of the pilot or crew such as ability to communicate effectively, or manage workload. Although this was recognised many years ago, non-technical skills remained a small part of pilot assessment until relatively recently (under headings such as ?airmanship?). The only realistic method available was the observation of crew behaviour, and this is still the case today. There are major problems with this method, mostly stemming from its subjective nature; for example it is not an inherently reliable system (one trainer may judge things very differently to another, or even themselves on a different day). In an attempt to resolve these issues, scientifically established methods of behavioural observation were adapted for use within aviation training and assessment. A well-established scientific method for recording and analysing behaviour is the construction of lists (or taxonomies) of behaviours that the scientists expect to see (the items in the list can be called behavioural descriptors). The observer refers to the list while watching the activity (or a recording of it) and notes each of the behaviours as they notice them occurring. Reliability and consistency of the descriptors is usually scrutinised statistically (i. Using scales of this sort, scientists can produce data about peoples? behaviour, and this can be analysed alongside factors such as peoples? performance. The adjustment of this sort of methodology for assessing the behaviour of a flight deck crew during a single session is still debated, but is nevertheless firmly established in the form of behaviour marker systems. Hence, a key principle of the system is that trainers are able to recognise the behaviours consistently in the training environment. Many marker systems have been produced and a variety of consistency measures have been attempted in order to demonstrate their consistency. It was subsequently used as the basis for many airlines? behaviour marker schemes (Flin and Martin 2001). Bottom lines thorough were established Plans stated Operational plans and decisions Shared understanding about P-D were communicated and plans. Used all available threats to safety resources to manage threats Monitor/crosscheck Crew members actively Aircraft position, settings, and P-T-D monitored and crosschecked crew actions were verified systems and other crew members Workload management Operational tasks prioritised and Avoided task fixation. Did not P-T-D properly managed to handle allow work overload primary flight duties Vigilance Crew members remained alert of Crew members maintained P-T-D the environment and position of situational awareness the aircraft Automation management Automation was properly Automation setup briefed to other P-T-D managed to balance situational members. Asks other crew members for options Risk assessment/option choice Considers and shares risks of alternative courses of action Table 4. It is composed of four categories (Cooperation, Leadership and Managerial skills, Situational Awareness and Decision Making). Additional to the effective transmission of information by the trainers, learners must engage with the content in order to properly understand and accept it. It is sometimes said that style of delivery is more important than content of a training session. Unfortunately it is still common for a skilled facilitator to run a superbly enjoyable and seemingly thoughtful session after which participants fill in fine reviews, but from which they recall little of value the day after. Transfer knowledge/skills Gain insight/self-analysis to enable an attitude change 3 Who knows the subject? Differences between Instruction and Facilitation (Dismukes and Smith 2000) Once the trainer has decided on effective content including achievable objectives, they should consider the most effective ways to deliver it. The method of delivery will depend upon what is being taught, and what the objectives are. Instruction can be described as being primarily a telling activity, where information is communicated to trainees through either direct communication or demonstration, with questioning primarily used to check understanding or reinforce key messages. Facilitation on the other hand, can be described as a technique that helps trainees to discover for themselves what is appropriate and effective, in the context of their own experience and circumstances. Instruction is the most efficient technique to employ for straightforward knowledge transfer; it would be laborious and unnecessary to teach a straightforward and precise subject such as an electrical system using facilitation. Instruction is quick and efficient, and can be used to train larger numbers of people. However trying to teach appropriate attitudes using instruction is difficult, particularly if the instructor does not have the authority or credibility required. To facilitate well, a trainer starts by deciding on objectives; what a successful session would achieve in terms of audience knowledge, understanding or attitude. They then decide what needs to be done in order for the participants to achieve these objectives by themselves. The audience can gain their own understanding by engaging in activities, such as answering well-framed questions or analysing data or case studies that the trainer has prepared. The skill of the trainer is to prepare and guide the session in a way that allows discovery of the desired points by audience members, but avoids generating a lot of off-task discussion (wasting time), unsolvable disagreements, or the audience reaching the opposite conclusions to those desired. These are all dangers of facilitation, and trainers must therefore plan and act carefully. The following four facilitation skills should be practiced and used whenever possible: 1. Effective Questioning Asking the right questions at the right time is a fundamental skill of facilitation. The nature of open questioning lends itself to long and detailed explanations where these are required. Closed Questions Closed questions are those where the possible answers are restricted or even implied. Closed questions are used to check understanding or to invite short and controlled contributions. Closed questions often start with words / phrases such as ?do you, don?t you, did it, was it. Facilitators must be careful not to narrow the possible responses to an open question by following it up with a closed one; a skill of a facilitator is to obtain more information to the original question without changing it. Hence to develop an answer, facilitators should use open and objective phrases such as ?tell me more about that?, or ?what are the reasons behind that? Listening It is frustrating for participants if a trainer appears unable to listen and engage with participants? views. It has often been said that hearing is done with your ears whereas listening is done with your mind. In this respect the term active listening means that a person is concentrating carefully on what is being said, so that they can really understand the other person. Observation of behaviour the ability to observe and discuss behaviour and attitudes as well as technical issues is a skill that trainers need to practice to become effective facilitators. Role modelling the importance of role-modelling was discussed in Chapter 13, and it applies to an instructor or trainer in the same way as others. Students should observe appropriate ways of acting and communicating and experience the positive effects on themselves. If participants appear to be giving no criticism then the following possibilities should be considered:? The trainer is not respected enough (feedback is considered ?not worth the effort?)? The trainees believe there is nothing to be gained from feeding back Feedback that is collected in a simple way, straight after a session (often known as happy sheets) should be treated with caution because it often reflects emotionally affected responses that bias the reactions. People who enjoyed being in a session will tend to state that the session content was useful.

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The surge in surge of plasma T4 levels that begins after hatching plasma T4 levels precedes the increase in plasma T3 and lasts for approximately the? In ring Obregon & Escobar del Rey, 1987), the horse doves, although total plasma T4 concentration does (Irvine & Evans, 1975), the ferret (Kastner, Kastner not demonstrate a pronounced peak, there is an & Apfelbach, 1987) and the lamb (Wrutniak, eightfold increase in free T4 levels peaking at Cabello & Bosc, 1985). In the rat, which is an approximately day 14 after hatching, that is sug altricial eutherian, these hormone surges commence gested to be due to displacement from plasma before birth but predominantly occur in the? In the brates, there is a severalfold increase in plasma T4 marsupials, the young are born at a very immature concentration during early vertebrate development phase and undergo a large amount of development which is either followed by, or coincident with, an in the pouch of the mother. The plasma T4 surge is time of pouch exit, rather than birth, that the more prevalent in vertebrates than a developmental physiological development of marsupial young is surge in plasma T3 levels. Deiodinase activity also varies during vertebrate Marsupial pouch young have been likened to development. In larval lampreys, outer ring (5h) ?exteriorised embryos? and have been proposed as deiodination activity is high in the intestine and liver good model systems in which to study mammalian and low in kidney and muscle, whilst in adult development (see Tyndale-Biscoe & Janssens, 1988). In very early pouch young deiodination activity was not detected in larval (well before histological development of the thyroid tissues but was observed in adult intestine and, to a gland), plasma T4 concentration is similar to adult lesser extent, in adult kidney (Eales et al. Thyroid hormone levels and tissue deiodination activity during development of the tammar wallaby Macropus eugenii. Young wallabies are at a stage physiologically similar to newborn eutherian mammals at this time. Tissue thyroid hormone levels do not echo tissue deiodinase activities are probably important in plasma concentrations during this period (Specker, determining di? During the parr-smolt intracellular thyroid hormones in individual tissues transformation, there is enhanced outer ring 5h during the parr-smolt transformation in salmonid deiodination activity in liver and heart, but in gill? Plasma T3 levels are conversion of T4 to T3 in premetamorphic tadpoles correlated with liver 5h-deiodination activity and yet both exogenous T4 and T3 had e? Inner ring 5-deiodination ac strated that outer ring 5h-deiodinase activity was 584 A. Hulbert absent in liver, heart, kidney and tail during derance of inner ring 5-deiodination prior to meta premetamorphosis but was present in skin and morphic climax to predominantly outer ring 5h exhibited minimal activity in brain and intestine deiodination after climax. At meta Japanese quail, at the time of the T4 surge around morphic climax, induced by T4 exposure, 5h the time of hatching there is also a dramatic increase deiodinase activity dramatically increased in skin in outer ring 5h-deiodination in the liver, which is and intestine and was present in tail but remained initially due an small increase in D2-type deiodinase absent in liver, heart and kidney, whilst 5-deiodinase but is rapidly replaced by a much larger increase in activity became barely detectable (Galton & Hie D1-type deiodinase activity. Galton (1988) examined tissue de activity, the D1 deiodinase declines to adult levels iodinase activities during spontaneous metamor during the? In the phosis and extended measurements to include pro altricial ring dove, hepatic 5h-deiodinase activity is metamorphosis and adult tissues. She found that 5h relatively constant in embryos and for a few days deiodinase activity was highest in skin and intestine after hatching after which it declines in activity. In prometamorphic decline in 5h-deiodinase activity after hatching in tadpoles, deiodinase activity was comparable to that this species is the opposite of changes in the serum in premetamorphic tadpoles and it remained high in T3T4 ratio which shows an increase during this adult tissues. In the adult frog, whilst 5h-deiodinase period (McNabb, 1988) this is probably due to the activity was only observed in intestine and skin, even more dramatic decline in 5-deiodination which inner ring 5-deiodinase activity was present in all will remove T3 formed from T4. Unexpectedly, in view of the week of incubation, the chick embryo liver shows a observation that 5-deiodinase activity decreases substantial increase in outer ring 5h-deiodinase during metamorphic climax, it has been shown that activity, whilst there is an even more dramatic 5-deiodinase (D3) gene expression and D3 enzyme decrease in inner ring 5-deiodinase activity over the activity is increased by exposure to T3 (Becker et al. A decline in 5h-deiodinase supported the concept that coordinated development activity following hatching is also reported for the of di? In this excellent study, the authors 5-deiodination is even greater and begins approx showed that some tissues. In the newly D2 deiodinase activity prior to, and negligible hatched chicken, hepatic 5-deiodination is negligible activity after metamorphic climax, whilst other (Darras et al. In the chicken, kidney relatively constant activity throughout the various deiodinase activity is less than that found in liver and stages of amphibian development. The activity of is relatively constant before and after hatching the inner ring D3 deiodinase also showed a de (Darras et al. Prior to metamorphic climax there is a eugenii neither liver nor kidney demonstrate any in decline in liver 5-deiodinase activity whilst after vitro 5h-deiodinase activity. However, at approx metamorphic climax there is an increase in 5h imately the time of the plasma T4 surge, in vitro 5h deiodinase activity in skin and intestinal tissue deiodinase activity increases in both liver and kidney (Galton, 1992a). Indeed, in the rat, the development of 5h there is a shift in emphasis from inner ring to outer deiodinase activity has di? Furthermore, the amount of transcript for both declines from being responsible for 100% of liver T3 types of receptors increases in the presence of T3. This thyroid hormone during development, the most notable being the responsiveness of thyroid receptors will result in the central nervous system. Brain receptor number thought that maternal thyroid hormones did not increased threefold from day 14 to day 17, after cross the placenta of eutherian mammals and were which it remained constant until after birth when it thus not important. However, the extensive studies rapidly increased to approximately adult levels by of Morreale de Escobar and Escobar del Rey and Thyroid hormones and their e? The neuronal cyto absence during early fetal life can have devel skeleton includes microtubules and micro? Actin is particularly important in half of their gestation (Bonet & Herrera, 1991). Normal neurite growth de the rat brain at birth is at the same stage as the pends both on the synthesis of cytoskeletal proteins human brain at 5?6 months of gestation and and on their axonal transport. Axonal transport of consequently, stages of brain development that take tubulin has been measured in the optic nerve of the place during the last trimester of human devel hypothyroid hythyt mouse and found to be sig opment occur postnatally in the rat. Many of these the early work of Eayrs and Legrand in the 1960s proteins have a number of isoforms that are expressed demonstrated that thyroid de? If rats compared to euthyroid control rats during the T4 replacement is initiated at postnatal day 12, then? In the rate of growth of neurite outgrowths and thus the vitro transcription measurements demonstrate a rate of migration of neurones towards their synaptic depressed actin gene transcription in hypothyroid targets. The impaired growth and arborization of cerebra that can be remedied by incubation of nuclei 588 A. By contrast, in vitro tubulin gene tran presence of T4 and the high levels of rT3 present scription rates are similar in hypothyroid and (largely due to the predominance of inner ring over euthyroid cerebra and incubation of nuclei with T3 outer ring deiodination) during early development has no e? This has an important functional role in facilitating suggests that whereas transcription represents an interaction between body cells and the extracellular important level of thyroid hormone control of the matrix. This Neural networks are formed by neurite growth includes the cerebellum, where the external germinal cones migrating along predictable routes to form layer persists and remains the site of mitosis for an synapses with speci? In germinal this migration are determined by proteins of the cells, thyroid hormones a? Myelogenesis essential for synapse formation and cell survival as is also retarded in hypothyroidism. In unresponsive to thyroid hormones prior to birth in both cases, T4 and rT3 are considerably more rats (Schwartz, Ross & Oppenheimer, 1997). Hypothyroidism during development also com One such study, however, suggests that the thyroid monly results in deafness. Postnatal rats made hormones play a role in olfactory learning and hypothyroid from late-fetal stages show no auditory imprinting in salmonid? Little is known of the embryonic myosin isoforms are replaced by neonatal precise cellular targets of thyroid hormone e? In rats, the postnatal surge in plasma T4 In normal rats, cochlear potentials following audi concentration coincides with the transition from tory stimulation have been recorded from postnatal neonatal to mature fast myosin isoforms in fast day 9 but in hypothyroidism no cochlear potentials muscles and is retarded by hypothyroidism and could be elicited during the? The times of such transitions vary between tons at the level of the cochlear outer hair cells (Uziel muscles and hypothyroidism delays, whilst hyper et al. In the brain itself, hypothyroidism thyroidism accelerates, such transitions (d?Albis et results in a decreased number and abnormal dis al. Similarly, in humans, hyperthyroidism tribution of apical shaft spines in pyramidal cells of has been shown to result in precocious accumulation the auditory cortex (Ruiz-Marcos et al. Although hypothyroidism retards develop responsive to thyroid hormone replacement and it mental changes in myosin expression in chick was suggested that the auditory cortex pyramids embryo skeletal muscles (Gardahaut et al. In damage, than other cerebral or cerebellar neurones amphibians, a moderate increase in thyroid hormone and structures. Administration dramatic increase in the ability of the sarcoplasmic of T3 during this period had no e? Interestingly, this developmental response of of the sarcolemmal Na+Ca#+ exchanger. Developmental regulation of cation pumps in It has been shown that T3 is a potent stimulant for skeletal and cardiac muscle has been reviewed by embryonic myoblasts to di? When various bones and cartilage are the importance of the developmental thyroid removed from one-day-old neonatal rats and trans hormone surge for muscle maturation has also been planted under the kidney capsule of euthyroid and shown in the precocial sheep where this T4 surge hypothyroid rats it was shown that the growth and occurs prenatally.

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The main gap in the evidence is the lack of convincing data from controlled trials that early treatment improves outcomes for patients with subclinical hypothyroidism and subclinical hyperthyroidism detected by screening. Association between thyroid dysfunction and total cholesterol level in an older biracial population: the health, aging and body composition study. Screening for thyroid dysfunction: Rationale, strategies, and cost effectiveness. Screening for mild thyroid failure at the periodic health examination: a decision and cost-effectiveness analysis. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? Clinical significance of a low serum thyrotropin concentration by chemiluminometric assay in 85-year-old women and men. Low serum thyrotropin (Thyroid-Stimulating Hormone) in older persons without hyperthyroidism. Serum free thyroxine and thyrotropin concentrations in a representative population of 81-year-old women and men. American College of Physicians [published erratum appears in Ann Intern Med 1999 Feb 2;130(3):246]. Thyroid dysfunction in ambulatory elderly Chinese subjects in an area of borderline iodine intake. Subclinical hypothyroidism in flight personnel: evaluation for suitability to fly. The prevalence of thyroid dysfunction in a population with borderline iodine deficiency. Prevalence of subclinical hypothyroidism in a population living in the Milan metropolitan area. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Low thyrotropin levels are not associated with bone loss in older women: a prospective study. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis. Effect of endogenous subclinical hyperthyroidism on bone metabolism and bone mineral density in premenopausal women. Bone mineral density in patients with endogenous subclinical hyperthyroidism: is this thyroid status a risk factor for osteoporosis? Clinical and socioeconomic predispositions to complicated thyrotoxicosis: a predictable and preventable syndrome? Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. The clinical evaluation of patients with subclinical hyperthyroidism and free triiodothyronine (free T3) toxicosis. Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with non-toxic nodular goitre. Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. The relationship between serum cholesterol and serum thyroid hormones in male patients with suspected hypothyroidism. Relations between thyroid function, hepatic and lipoprotein lipase activities, and plasma lipoprotein concentrations. The relationship between serum cholesterol and serum thyrotropin, thyroxine, and tri-iodothyronine concentrations in suspected hypothyroidism. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Determinants of changes in plasma homocysteine in hyperthyroidism and hypothyroidism. Effect of treatment of hypothyroidism on the plasma concentrations of neuroactive steroids and homocysteine. Homocysteine, folate, vitamin B12, and transcobalamins in patients undergoing successive hypo and hyperthyroid states. Long-term residual complaints and psychosocial sequelae after remission of hyperthyroidism. Relation of severity of maternal hypothyroidism to cognitive development of offspring. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Bone metabolism during anti thyroid drug treatment of endogenous subclinical hyperthyroidism. Normalization of serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism: effect on bone loss in postmenopausal women. Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. A study in normal human volunteers to compare the rate and extent of levothyroxine absorption from Synthroid and Levoxine. Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumulative meta-analyses. Bone density is not reduced during the short-term administration of levothyroxine to postmenopausal women with subclinical hypothyroidism: a randomized, prospective study. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled trial. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. Clinical response to thyroxine sodium in clinically hypothyroid but biochemically euthyroid patients. Symptoms and Signs of Thyroid Dysfunction Hypothyroidism Hyperthyroidism Symptoms Coarse, dry skin and hair Nervousness and irritability Cold intolerance Heat intolerance Constipation Increased frequency of stools Deafness Muscle weakness Diminished sweating Increased sweating Physical tiredness Fatigue Hoarseness Blurred or double vision Paraesthesias Erratic behavior Periorbital puffiness Restlessness Heart palpitations Restless sleep Decrease in menstrual cycle Increased appetite Signs Slow cerebration Distracted attention span Slow movement Tremors Slowing of ankle jerk Tachycardia Weight gain Weight loss Goiter Goiter 48 Table 2. Quality of Randomized Trials of Thyroxine Replacement Therapy Eligibility Outcome Study, Random Allocation Groups Similar at Criteria Assessors Care Provider Year Assignment? Quality of Randomized Trials of Thyroxine Replacement Therapy (continued) Reporting of Attrition, Differential Loss to Score Patient Intention-to-Maintenance of Crossovers, Follow-up or Overall Statistical (Good/ Study, Unaware of Treat Comparable Adherence, and High Loss to Follow-Analysis Fair/ Year Treatment? Poor) Cooper et al, Yes, not No the number of Partially Unclear, probably not Yes, except it Good 1984(75) verified patients randomized did not address appears to be 41; 33 dropouts patients were analyzed. Description and Results pf Randomized Trials of Thyroxine Replacement Therapy (continued) Quality Adverse Rating Study, Effects (Good/Fair/ Relevance Year Assessed? No known history or not stated Jaeschke et al, Only through 1 case of atrial Fair Fair Description of Were patients referred 1996(15) dropouts fibrillation and 1 case recruitment was from family practitioners? Summary of Findings of Systematic Review Overall Level and Type of Evidence for Arrow* Question Evidence the Link Findings 1 Is there direct None N/A No controlled studies links screening directly to health evidence from outcomes. It also detects unsuspected subclinical hyperthyroidism in 5-20 per 10,000 adults. Subclinical hypothyroidism is found in 5% of women and 3% of men; the yield varies with age and is highest in elderly women.

References:

  • https://www.midus.wisc.edu/findings/pdfs/1153.pdf
  • https://www.ecronicon.com/ecmi/pdf/ECMI-14-00450.pdf
  • https://zu.edu.jo/UploadFile/Library/E_Books/Files/LibraryFile_9134_13.pdf
  • https://books.google.com/books?id=XuGdAgAAQBAJ&pg=PA294&lpg=PA294&dq=Laryngeal+Cancer+.pdf&source=bl&ots=CqagRBO8pn&sig=ACfU3U0Ohoq2eLYoJ8osHnYE1TvjNWIQjA&hl=en
  • https://dash.harvard.edu/bitstream/handle/1/15821596/GOYAL-DOCTOROFMEDICINETHESIS-2015.pdf?sequence=4

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