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In table 4 effective 260 mg extra super avana, we reproduce a similar specification as in table 3 extra super avana 260 mg, panel A at the firm level generic extra super avana 260 mg. The main difference with respect to the sector-level analysis is that Country Meritocracy is now replaced by Firm Meritocracy (we explain its construction in section 1 and table 1). Apart from the fact that this variable varies at the firm level, a distinct advantage of it is that it reflects factual information about firm characteristics, as opposed to perceptions. As figure 6 shows, Italy exhibits a distribution of this firm-level meritocracy that is much more left-skewed than the other countries in our sample. The firm-level meritocracy is highly correlated with the country- level one (see figure 7). In table 5, column 2, we add, as a control variable, the percentage of employees with a college degree. If that effect exists, it is captured, in our regression, by the country fixed effects. To correct for the attenuation bias of the standard errors-in-variable problem, we need to make an assumption on the reliability of the measurement of the variable Country Meritocracy. Since the squared correlation between the country- level meritocracy and firm-level meritocracy is about 50%, we assume this reliability to be 50%. Thus, the “meritocracy” 19 effect explains between 61% and 83% of the Italian gap. If this is the case, why did Italian firms fail to adopt superior managerial techniques? This explanation has the advantage of containing the hope that, in the long run, the adaptation will take place, even absent policy interventions. If this were the case, then convergence in the long run will not occur without a policy intervention. The most obvious one is that loyalty- based management can function better in environments where legal enforcement is either inefficient or unavailable. Among developed countries, Italy stands out both for its inefficient legal system (the average time to enforce a contract, as measured by Djankov et al. To corroborate this hypothesis, we need to find a way to measure the differential benefit of being loyalty-based in Italy. We focus on three external constraints, namely: financial constraints, labor regulation, and bureaucracy. In table 6, we estimate, using a probit model, the conditional probability that the firm 20 encounters each of these constraints. Beside sector fixed effects, the key explanatory variables are the firm level of meritocracy, and its interaction with a dummy for Italy. The interaction between the meritocracy index and the Italy dummy is very similar in magnitude, but opposite in sign, to the baseline coefficient of meritocracy. Interestingly, this interaction effect for Italy is significant for financial constraints and bureaucratic constraints, but not for labor market constraints. Loyal management can exchange favors with banks and bypass bureaucracy through political connections or bribes, but finds it more difficult to overcome the constraints that labor regulation puts on growth. These results are hardly proof that loyalty-based management is advantageous in Italy, but they are consistent with this assumption. Conclusions In this paper we try to explain why 20 years ago Italian productivity stopped growing. We find no evidence that this slowdown is due to international trade developments. We also do not find any evidence supporting the claim that excessive protection of employees is the cause. In this sense, the Italian disease is an extreme form of the European disease identified by Bloom et al. We find evidence for this hypothesis using both country/sector-level data and firm-level data. Our evidence suggests that even today un-meritocratic managerial practices provide a comparative advantage in the Italian institutional environment. In sum, the explanation for the Italian disease most consistent with the data is that Italy suffers from an extreme form of the European disease identified by Bloom et al. In other words, familyism and cronyism are the ultimate cause of the Italian disease. Djankov, Simeon, Rafael La Porta, Florencio Lopez-de-Silanes, and Andrei Shleifer. García-Santana, Manuel, Enrique Moral-Benito, Josep Pijoan-Mas, and Roberto Ramos. Industry growth rates are weighted at the country level using hours worked in the initial year. Growth across sectors is unweighted, in order to factor out the sectoral composition of the economy. We use articles from the years 2000–2012 from Bloomberg, Dow Jones, Financial Times, Reuters, Thomson Financial, and the Wall Street Journal sourced from the Factiva news search database. Agriculture, Hunting, Forestry and Fishing Chemicals and Chemical Products Electricity, Gas and Water Supply Construction Transport Equipment Manufacturing Nec; Recycling Financial Intermediation Electrical and Optical Equipment Post and Thelecommunications Transport and Storage Real Estate, Renting and Business Activities Coke, Refined Petroleum and Nuclear Fuel Food, Beverages and Tobacco Machinery, Nec Mining and Quarrying Pulp, Paper, Printing and Publishing Wholesale and Retail Trade Hotels and Restaurants Rubber and Plastics Thextiles, Leather and Footwear Wood and Products of Wood And Cork Basic Metals and Fabricated Metal 0. If the percentage of managers affiliated with the controlling family is not reported, we use 1 minus the percentage of managers not affiliated with the controlling family (if this is reported). If this is also missing, but the absolute levels are reported, we compute the percentage ourselves from the absolute figures. Government Dependence Ratio of government-related news to total sector news in a pool of articles Factiva News Search from Bloomberg, Dow Jones, Financial Times, Reuters, Thomson Financial, and the Wall Street Journal from the period 2000–2012. We define as government-related news items that have at least one of the following subject tags in the Factiva news database: 1) government policy/regulation, 2) government aid, 3) government contracts. It is World Economic Forum, computed by the World Economic Forum using country data on mobile 2012 network coverage, the number of secure internet servers, internet bandwidth, and electricity production. Management Schools Average of Global Competitiveness Report Expert Survey (2012): World Economic Forum, “In your country, how do you assess the quality of business 2012 schools? At the firm level, it is computed by us as the residual growth in output (revenues at constant prices) after deducting the contributions of capital (measured as fixed assets at constant prices), labor (measured as labor expenditure at constant prices), and other inputs (measured as the residual costs at constant prices). Employment Laws, Government Inefficiency and Country Meritocracy vary at the country level. Because source data for ΔTrade Exposure and ΔRule of Law begin in 1995, we use, for the regression in panel C, their values in 1996–2006 as a proxy for those in 1985–1995. Panel C regressions have fewer observations because growth accounting series are unavailable before 1995 for some countries/sectors. In table 1-bis, we provide variable descriptions for the additional variables utilized. Tables 3A-bis and 3B-bis replicate the analyses of tables 3A and 3B using alternative measures of Employment protection laws, change in the quality of government and exposure to foreign competition. The rationale for this specification is to perform a test of the “parallel trend assumption”. To use a diff-in-diff analogy, while in table C we let the “treated sectors” vary between the pre-treatment period and the post-treatment period, here we impose they be the same, as it would happen in a traditional diff-in-diff specification. Table 3A-ter replicates the analysis of table 3A, by excluding three emerging European countries for which data is not available in the pre-treatment period 1985–1995 (Czech Republic, Hungary, Slovenia). The dataset includes 3 more countries (Korea, Luxembourg, Portugal) but 2 fewer sectors (most of the services sectors are absent). This interaction control variable captures the possibility that labor reallocation, over the period 1996–2006, was most needed in sectors which were most exposed to increased competition from Chinese imports. The rationale behind the inclusion of this interaction variable is that the main channel through which opening of trade might have caused a slowdown in productivity among developed countries, outside labor reallocation, is economies of scale. In the same table, we also show that our results are robust to controlling for the effect of two alternative measures of the quality of government. Differently from the measures used in table 3A and 3A-bis, these two measures are derived from a single source and capture the level, as opposed to the change, in the quality of public services. Tables 4-bis and 5-bis replicate the analyses of tables 4 and 5 adding the size of the firm (measured as the log number of employees) as an additional control variable.

Survival is the usual primary focus of disease prevention and Survival is one of several competing goals buy cheap extra super avana 260 mg line. Disease management becomes creased physical activity order extra super avana 260 mg with visa, and decreased alcohol intake); one of several means towards the end goal buy extra super avana 260 mg with mastercard, rather than, as preventive services (e. In the disease model, the patient’s tions such as aspirin, statins, calcium, vitamin D, and “chief complaint” leads to the creation of a differential bisphosphonates, which are all predicated on preventing diagnosis. Under a more individually tailored cillary tests help to determine which diseases most likely model, preventive decision making is based on a patient’s explain the patient’s symptoms or complaints. Treatment articulation of preferred trade-offs between long-term then is aimed at this underlying disease. In the integrated, outcomes such as survival or functioning and short-term individually tailored model, the patient’s complaints ini- acceptance of testing burden, lifestyle changes, and the tiate three sets of questions. The first set asks in what ways inconvenience, costs, and side effects of daily medica- the complaints are bothersome—what is the effect on the tions. The details of how clinical encounters will be struc- patient’s physical, psychological, and social functioning? What trade-offs are the patient willing The need to ascertain and incorporate individual pri- to make? In the case of prevention, does the patient value orities, to address multiple contributing factors simulta- “down the road” benefits more or does the patient have neously, and to prescribe and monitor multifaceted in- more immediate concerns about the side effects of daily terventions will make clinical decision making more medications? The third set of questions explores the non- iterative, interactive, individualized, and complex. For example, are psy- ative use of information technologies should facilitate the chological or social factors further impeding health and organization, presentation, and integration of this infor- functioning? The answers to these questions are integral mation to arrive at individualized yet systematic clinical to constructing the treatment plan. Examples of clinical decision making predicated on individual patient priori- decision making under these contrasting models are ties. To accomplish its goals, health care must be- The integrated, individually tailored approach also ap- come more interdisciplinary. Clinical Decision Making with the Disease-Oriented and Integrated, Individually Tailored Models for a 44-Year-Old Obese Man Reporting Decreased Activity Tolerance Disease-Oriented Model Integrated, Individually Tailored Model Collect clinical data Collect patient-specific data ● History (e. The increased emphasis on psychological, so- will be needed in the training of other health profession- cial, environmental, and other factors will raise concerns als. Al- Research, along with clinical care, has shaped the de- though necessitating a delineation of the components of partmental structure of medical schools, which in turn health, the debate should revolve not around medicaliza- has influenced the organization of clinical practice. Re- tion or interdisciplinary “boundaries,” but around efforts search is, however, already restructuring along method- to coordinate and pay for efficient and effective interdis- ological and technological lines, and away from an organ- ciplinary care, whether it is provided within or outside and specialty-based configuration. Medical education, for example, which can thus evolve unencumbered by the need to artificially has been organized around pathophysiologic mecha- fit into a research-driven paradigm. These changes are primarily in re- coverage and payment decisions should follow logically sponse to time constraints and information overload and from a clear articulation of the goals and structure of care. Nevertheless, it is worth taking advan- nity, perhaps for the first time, to articulate coverage de- tage of this transition to train the next generation of phy- cisions based on evidence of effectiveness and on trans- sicians, who are not yet wedded to the disease model, in a parent societal and personal priorities. Clinical Decision Making with the Disease-Oriented and Integrated, Individually Tailored Models for a 76-Year-Old Woman with Fatigue and Weight Loss Disease-Oriented Model Integrated, Individually Tailored Model Collect clinical data Collect patient-specific data ● History (e. Determining the boundaries of which both biologic and nonbiologic factors operate. The organization, Paradoxically, two anticipated arguments against payment, and quality assessment of medical care remain change will be that “this is nothing new, we already do firmly entrenched in disease-specific, episodic care. Dizziness among older adults: a the benefits that accrue from targeting the basic mecha- possible geriatric syndrome. The relative influence of perceived pain nisms of disease, it is na¨ıve to think that this strategy alone control, anxiety, and functional self-efficacy on spinal function will obviate the need for a more individualized, interdis- among patients with chronic low back pain. Acute myocardial infarction: number of persons with a heavy burden of illness and psychosocial and cardiovascular risk factors in men. What will be the impetus for tors on the pathogenesis of cardiovascular disease and implications embarking on the daunting task of transforming the for therapy. Neighborhood of resi- possible scenario is that with diverse motivations, medi- dence and incidence of coronary heart disease. The ever expanding array of expen- den death by a multifactorial intervention programme after myo- sive technologies available for an increasing number of cardial infarction. A meta-analysis of psy- boomers who will rapidly overwhelm a health care system choeducational programs for coronary heart disease patients. Psychosocial interventions for pa- tients with diverse health priorities to participate in clin- tients with coronary artery disease: a meta-analysis. A report of the American College of Cardi- Perhaps the greatest barrier will be that the disease ology/American Heart Association Task Force on Practice Guide- model is so entrenched that most clinicians and patients lines. Comparison of two model, developed as a means of translating emerging sci- aspirin doses on ischemic stroke in post myocardial infarction pa- tients in the warfarin (Coumadin) aspirin reinfarction study. The sixth report of the Joint National Commission on prevention, grated model based on the health care needs of patients in detection, evaluation and treatment of high blood pressure. Treatmentofdysthymiaand ment-tradeoff method to elicit preferences for the treatment of lo- minor depression in primary care: a randomized controlled trial in callyadvancednon-small-celllungcancer. A patient-centered approach to investigations to diagnose the cause of dizziness in elderly people: a advance medical planning in the nursing home. Shared risk factors for falls, incon- decision aid for patients with atrial fibrillation who are considering tinence, and functional dependence. Gastrointestinal illness and the biopsychosocial measuring clinically important changes in the frail elderly. Immunisation contacts and resources Specifc questions on immunisation should be directed to your immunisation provider (doctor or child health nurse), your local public health unit, or to the Central Immunisation Clinic on telephone 9321 1312. A range of publications and information on immunisation can be accessed and/or ordered through: Department of Health www. While every reasonable effort has been made to ensure the accuracy of the information in these guidelines, no guarantee is given that the guidelines are free from error or omission. The information provided is not a substitute for medical care and so specifc questions about a person’s health status should be directed to their health care provider. Notifable diseases outlined in this book may be followed up by a public health unit staff member. While it is often diffcult to prevent the transmission of common respiratory (colds/fu) and gastroenteritis infections that occur, every effort should be made to minimise the spread of infection by encouraging: * staff and children attending school or childcare should stay at home in the early stages of illness as they are likely to be more infectious and transmit the virus/bacteria to others, via coughing, sneezing and, contaminating surfaces that others touch * staff working in schools or childcare organisations, including the children, should remain absent until they are symptom free if they have a cold or fu; and for at least 24 hours if they have had gastroenteritis * parents to seek medical advice if their child has ongoing symptoms of illness * follow up by the local public health unit for other important infections, including measles, whooping cough, meningococcal and typhoid infections (telephone numbers on page 3). Many childhood infectious diseases require students/staff to be excluded from day care or school for a recommended period of time; if they are unable to provide evidence of immunisation against specifc diseases that are known to be highly transmissible they will be excluded. If unsure about what action to take, contact your local public health unit (telephone numbers on page 3). Strategies to prevent transmission of infection: * Hand washing with soap and water for at least 15 seconds before preparing or eating food, after using the toilet, changing nappies, after blowing your nose with a hanky or tissue (disposable tissues are preferred), and after any contamination of the hands with body fuids such as blood and vomit. Symptoms include fever, malaise, chills, headache, muscle pain, sore throat, cough and diarrhoea. Symptoms include fever, fatigue, and a generalised rash characterised by small vesicles (blisters) that rupture to form crusts. Transmission Airborne or droplet; direct or indirect contact with fuid from vesicles of an infected person Incubation Average 10–21 days period Infectious From 2 days before rash appears to period 5 days after, when vesicles have formed crusts. See Appendix 1 for immunisation recommendations Exclusion Exclude for at least 5 days after vesicles (rash) appear and until vesicles have formed crusts. Note that crusts alone do not warrant exclusion Treatment Antiviral treatment available Contacts Refer any immunosuppressed children (e. Do not exclude other contacts Immunisation Non-immune pregnant women should see their doctor urgently as immunisation may prevent chickenpox in contacts within 5 days of exposure. Post exposure immunisation can also be offered to other non-immune contacts to prevent disease 9 Communicable disease guidelines 2017 Edition Conjunctivitis C (various viruses and bacteria) A common, acute, viral or bacterial infection of the eyes. Transmission Direct or indirect contact with secretions from infected eyes Incubation 24–72 hours period Infectious While eye discharge is present period Exclusion Exclude until discharge from eyes has ceased Treatment Treatment as recommended by doctor – refer to doctor Contacts Do not exclude Immunisation None available 10 Communicable disease guidelines 2017 Edition Cryptosporidiosis C Notifable – discuss with your local public health unit staff. When present, symptoms include vomiting, loss of appetite, stomach pain and foul smelling diarrhoea.

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Morisco C cheap extra super avana 260mg fast delivery, Trimarco B order 260mg extra super avana overnight delivery, Condorelli M: Effect of coenzyme Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study purchase extra super avana 260mg overnight delivery, Clin Investig 71(suppl 8):S134-S136, 1993. Willis R, Anthony M, Sun L, et al: Clinical implications of the correlation between coenzyme Q10 and vitamin B6 status, Biofactors 9:359-63, 1999. The total body content of copper is pri- marily regulated by means of excretion rather than absorption. Copper is excreted attached to taurochenodeoxycholic acid, a sulfur-containing bile acid that is stored in the liver. When mobi- lized, copper is found in the plasma firmly attached to protein as cerulo- plasmin. Copper (Cu) plays a role in hemoglobin synthesis, neural function, glu- cose utilization, and skeletal and cardiovascular health. Copper salicylate is known to have analgesic and anti-inflamma- tory effects, and the efficacy of various copper-based anti-inflammatory drugs is under investigation. Its effi- cacy is often mediated by oxidation-reduction reactions in which Cu+ is con- verted to Cu2+. Copper is an essential component of superoxide dismutase, an enzyme that protects cell membranes by contributing to the breakdown of toxic free radicals, and cytochrome C oxidase, an enzyme of the electron transport chain involved in oxidative energy pro- duction ● Iron metabolism. Copper plays an important role in the oxidation-reduc- tion, mobilization, and transport of iron (Fe), which is stored as Fe3+, mobi- lized as Fe2+, and deoxidized as Fe3+ for transport as transferrin. Lysyl oxi- dase, a copper requiring enzyme, cross-links lysine in collagen and elastin. Additional copper can be obtained by drinking water that flows through copper pipes, by using copper cookware, and by eating farm products sprayed with cop- per-containing chemicals. The copper content of acidic foods decreases when they are stored in tin cans for long periods. The absorption of copper is reg- ulated by the thioneines, sulfur-rich binding proteins found in the intestinal lining and other body cells. The thioneines are responsible for binding cop- per, zinc, and various other divalent metals. The efficiency of copper absorp- tion is reduced by sulfides, ascorbic acid, zinc, and molybdenum. Both men and women fed diets close to 1 mg of copper per day experienced reversible, potentially harmful changes in blood pressure control, in cardiac electrical conduction as shown on electrocardiograms, cholesterol levels, and glucose metabolism. Animal studies also suggest that copper deficiency below a thresh- old level can induce atherosclerotic lesions. A longitudinal study of young men demonstrated that although most indices of copper status were unchanged, biomarkers of bone resorption were significantly increased on switching from medium (1. Nausea, abdominal and muscle pain, irritability, and depression may indicate copper toxicosis. Daily zinc supplementation of 150 mg over 2 years will precipitate copper deficiency. Similarly, simulta- neous use of oral zinc supplements with copper supplements may decrease copper absorption. Copper and zinc supplements should be taken at least 2 hours apart to obtain the maximum benefit from each. Persons receiving penicillamine or trientine should delay taking their medication until at least 2 hours have elapsed after administration of a copper supplement. However, the anemia is an iron defi- ciency anemia because iron stores lack the copper necessary for iron mobi- lization. Copper deficiency also presents with depigmented, grayish hair that has lost its regular wave. Weakened collagen and elastin predispose patients with copper deficiency to skeletal and vascular disorders. A useful indicator of copper status is the copper-zinc–superoxide dismu- tase level in erythrocytes, which is depressed in copper deficiency. Brighthope I: Nutritional medicine tables, J Aust Coll Nutr Environ Med 17:20-5, 1998. Baker A, Harvey L, Majask-Newman G, et al: Effect of dietary copper intakes on biochemical markers of bone metabolism in healthy adult males, Eur J Clin Nutr 53:408-12, 1999. More work is needed to clearly distinguish between the efficacy of various species and the different plant parts (roots versus upper plant parts) and to ascertain the bioavailability, relative potency, and syner- gistic effects of the active compounds. In vitro studies suggest that echinacea enhances the immune response and has an antiviral and weak antibacterial effect. Although echinacea has no direct bactericidal or bacteriostatic properties, in vitro studies have shown that it enhances phagocytosis, triggers proliferation of T lymphocytes, and increases macrophage release of tumor necrosis factor, interleukin 1, and β-interferon. Active constituents include caffeic acid derivatives, flavonoids, essential oils, polyacetylenes, alkylamides, and polysaccharides. However, the purity of some commercial products is doubtful; many have been found to be adulterated with various plant extracts. Furthermore, because active constituents vary slightly according to species and because 501 502 Part Three / Dietary Supplements echinacea’s immune-stimulating effect probably results from interaction between various constituents, standardization of an extract is problematic. Discrepancies in the source and dose of echinacea are, in fact, one explana- tion for the variable results found in reviews of placebo-controlled, random- ized studies investigating the immunomodulatory activity of echinacea preparations in healthy volunteers. Freeze-dried echinacea can be taken as one to two capsules or tablets three times daily. However, to prevent illness or to treat chronic conditions, any one of the following may be useful: 1 to 3 g/day dried root of E. Recent evidence suggests that echinacea is likely to be more effective when used therapeutically rather than for prophylaxis. Symptomatic relief is reported when therapy is initiated at the first sign of infection, but there is insufficient evidence to support prevention of respiratory tract infections by long-term prophylactic use of echinacea. A review of 12 clinical studies suggested that methodological prob- lems such as small populations and use of noncommercially available, non- standardized dosage forms make it difficult to determine whether echinacea provides effective therapy for upper respiratory tract infections. Such popularity among patients would seem to demand that professionals at least cautiously explore echinacea as an option offering immune support for persons with upper respiratory tract Chapter 61 / Echinacea 503 infections. A randomized, double-blind, placebo-controlled study demon- strated that echinacea concentrate and Echinaforce provided a low-risk and effective alternative to the standard symptomatic medicines in the acute treatment of the common cold. Allergic reactions are rare, but anaphylaxis and contact dermatitis have been reported. The possibility that cross- reactivity between echinacea and other environmental allergens may trigger allergic reactions in “echinacea-naive” subjects is supported by Australian data. Echinacea may exacerbate symptoms of autoimmune disorders such as lupus or rheumatoid arthritis and multiple sclerosis. It is considered prudent to avoid prescribing echinacea for patients having treatment with immuno- supressives including corticosteroids, cytotoxic drugs, and antiretroviral drugs. A review of the literature to determine the possible interactions between seven top-selling herbal medicines found no reported interactions between echinacea (E, angustifolia, E purpurea, E. Some authorities advise against taking echinacea for longer than 8 weeks; others believe that long-term ingestion is acceptable. Because prolonged use of echinacea may diminish its immune-boosting effects over time, another approach is to rotate echinacea with cat’s claw, goldenseal, astragalus, pau d’arco, or reishi and maitake mushrooms. Another potentially useful treat- ment protocol for patients with poor immunity is the following16: A daily maintenance dose of 5 mL of a 1:2 preparation (2. Double or triple the daily maintenance dose at the earliest suspicion of infection and only return to the maintenance dose once the threat has passed. If the infection progresses, maintain the higher dose until fully recovered, then return to the maintenance dose. Because parental administration alters blood sugar levels, patients with diabetes should take care when using any form of echinacea. Melchart D, Linde K, Worku F, et al: Results of five randomized studies on the immunomodulatory activity of preparations of Echinacea, J Altern Complement Med 1:145-60, 1995. Diefendorf D, Healey J, Kalyn W, editors: The healing power of vitamins, minerals and herbs, Surry Hills, Australia, 2000, Readers Digest. Hoheisel O, Sandberg M, Bertram S: Echinacea shortens the course of the common cold: a double-blind placebo controlled clinical trial, Eur J Clin Res 9:261-9, 1997. A randomized, placebo controlled, double-blind clinical trial, Phytomedicine 6:1-6, 1999. Barrett B, Vohmann M, Calabrese C: Echinacea for upper respiratory infection, J Fam Pract 48:628-35, 1999. Melchart D, Walther E, Linde K, et al: Echinacea root extracts for the prevention of upper respiratory tract infections: a double-blind, placebo-controlled randomized trial, Arch Fam Med 7:541-5, 1998. Mills S, Bone K: Principles and practice of phytotherapy, Edinburgh, 2000, Churchill Livingstone.

Factors contributing to basal membrane degradation that precedes the ulcer development are not known extra super avana 260mg without prescription. Introduction: Brucellosis is a zoonosis caused by bacteria of the genus Brucella that infects humans and a variety of animals discount 260mg extra super avana amex, mainly cattle order extra super avana 260 mg amex. According to World Health Organization, this illness remains the commonest zoonotic disease worldwide with thousands of new cases reported every year. In addition to great damages to health, Brucellosis affects the quality of animal-derived products resulting in a great economic impact, especially in Brazil. Thus, the goal of this study was evaluate the effect of Thalidomide treatment on immune response against B. The results have shown a significant decrease in the number of bacteria in the spleen of the treated animals compared to control group. Additionally, was detected an enhanced cytotoxic activity in splenocytes derived from treated animals. Conclusion: The results suggest that Thalidomide is able to potentiate the immune response against B. Unrevealing the immunopathological mechanism behind this mycosis may display new pharmacological targets and help to design more efficient and safer therapeutic approaches. The aim of this study was to evaluate the response of different macrophage models to T. Conclusion: Results showed that macrophages efficiently phagocytosed but did not eliminate the fungus. Even though activated macrophages could resist to fungal growth, they showed a fungistatical, but not fungicidal, activity. Complement represents a central immune mechanism in blood circulation, but the high ability of Leptospira to spread indicates a low efficacy of complement against this microorganism. Pathogenic Leptospira have successfully developed strategies to evade the complement system. However, complement evasion may also occur in the fluid phase, by the secretion of bacterial proteases. The aim of this work was to evaluate the Leptospira ability to secrete proteases that directly cleave complement molecules and also to identify the proteins responsible for the cleavages. Methods and Results: The proteolytic cleavages of complement molecules were analyzed by Western blot. In contrast, non-pathogenic Leptospira did not present significant proteolytic activity. The protease activity was inhibited by ortho-phenanthroline, a metalloprotease inhibitor. We cloned, expressed and purified the leptospiral metalloprotease thermolysin NprT and showed that it was able to cleave C3 and that its activity was inhibited by ortho-phenantroline. We also performed a purification of the native proteases from the pathogenic leptospiral supernatant by gel filtration. Finally, we showed the alternative pathway activity of normal human serum was reduced by the treatment with pathogenic leptospiral proteases. Conclusions: We describe a novel immune evasion mechanism in Leptospira: the secretion of proteases that cleave complement proteins. We also identified the thermolysin NprT, a metalloprotease that cleaves the complement molecule C3. The leptospiral proteases can be considered as virulence factors, since they can deactivate immune effector molecules, being potential targets to therapeutic approaches in leptospirosis. Host‟s immune system plays a critical role in parasitemia control; however, exacerbated cellular response can cause tissue damage. Interactions between the immune, nervous and endocrine systems play an important role in modulating host susceptibility and resistance to inflammatory and infectious diseases through the homeostasis maintenance of cellular response. Statistical analysis of data was performed using the chi(2) likelihood ratio test. Introduction: Toxoplasmosis is a worldwide disease, in immunocompetent individuals are asymptomatic and manifest in different clinical forms in pregnant women and immunosuppressed. In addition, regulatory T cells and anti-inflammatory cytokines act by regulating the immune response. The parasite load on days 5 (1,9x10 ±0,4x10 ) and 7 7 7 4 4 (2,6x10 ±0,9x10 ) was significantly higher compared to days 1 (2,3x10 ±1x10 ) 4 4 e 3 (6x10 ±4x10 ) p. Introduction: Visceral leishmaniasis is an emerging public health problem, with 500,000 new cases per year. Methods and results: Were evaluated 8 patients pre-treatment, 3 post-treatment and 8 healthy subjects. The percentage of body fat was lower in patients pre-treatment (16,3±10,6) compared to controls (27,4±6,3); phase angle was lower in patients pre- treatment (5. Patients also had nutritional profile changes that may be interfering with the immune response against the parasite. Introduction: Trypanosoma cruzi infection predominantly induces a Th1 response to control the parasite proliferation; nevertheless an exacerbated Th1 response is deleterious to the host. Introduction: Leishmania infections can result in a wide spectrum of clinical manifestations, and the outcome of disease is determined by parasite species and the host immune response. Draining lymph nodes and ears were isolated after 20 h, 1 and 3 weeks and cells were stained and analyzed by flow cytometry. Introduction: In the experimental model to study type 2 granulomas, mice are inoculated intraperitoneally and challenged intravenously with eggs of Schistosoma mansoni, previously isolated from liver of chronically infected animals. It is worth noting that uninfected individuals are found in all reported studies of endemic areas and the variation in seropositivity is attributable to genetic factors. To estimate the disease risk, odds ratio and 95% confidence interval were calculated. The Hardy-Weinberg equilibrium was achieved by calculating the expected genotype frequencies and comparing them to the observed values. Introduction: Eosinophils are important in the pathophysiology of allergic diseases and in host immunity. Although microorganisms directly activate inflammatory cells, the mechanisms that trigger eosinophils activation and its functions in immune responses are unknown. Fungi are ubiquitous and may contribute to the development and exacerbation of pulmonary diseases. In this sense, the aim of this study was to unravel the role of eosinophils during Aspergillus fumigatus lung infection. Interestingly, histopathological analysis did not show any differences between animals. Conclusion: In conclusion, the absence of eosinophils leads to decreased production of key cytokines and increased fungal burden after infection with A. However, this is associated with enhanced neutrophil influx and survival, suggesting that eosinophils are crucial in setting the appropriate tone of the immune response to infection by A. It is therefore important studying new alternatives for the treatment of infected dogs, which may reduce the incidence of the disease in endemic areas. Methods and Results: This investigation was performed in Araçatuba, the city is located in the São Paulo state. A group of 6 healthy dogs, from a non-endemic area were included in the study as negative controls. Introduction Toxoplasmosis is a zoonosis caused by an intracellular parasite, Toxoplasma gondii. Several studies have been performed in order to understand the interactions between proteins of parasite and its host cells. Additionally, It has been previously found to be serologically immunodominant during the acute phase of toxoplasmosis. In addition, distinct conformations of the loop were predicted within strain types of T. Additionally, we observed that overall structural homology was preserved in the N-terminal end of the sequences. Interestingly, the resistant isolates survived and proliferated better in murine macrophages, showing a significantly higher number of infected macrophages and parasite numbers.

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Transmission via close contact with infected persons (ocular or respiratory secretions) or contaminated fomites i effective extra super avana 260mg. Ocular symptoms 7 to 10 days after exposure to infected person/contaminated fomite d buy 260 mg extra super avana overnight delivery. Photophobia buy extra super avana 260mg otc, epiphora, foreign body sensation, and possibly reduced visual acuity (associated with subepithelial infiltrates) D. The diagnosis of adenovirus conjunctivitis is usually based on clinical findings 2. Laboratory testing may be used as an adjunct to clinical diagnoses when the physician needs to differentiate adenovirus conjunctivitis from other causes of acute conjunctivitis a. May exacerbate herpetic keratoconjunctivitis or bacterial conjunctivitis in case of misdiagnosis or coinfection a. Use only for visually significant (photophobia/reduced visual acuity) subepithelial opacities and conjunctival membranes b. Avoidance of transmission during period of viral shedding (7-10 days after onset of clinical signs and symptoms) 1. Bacterial infection of the eyelids caused usually by Staphylococcus aureus, but occasionally by coagulase- negative staphylococci B. Hard, brittle, fibrinous scales and hard, matted crusts surrounding individual eyelashes 2. Eyelid ulceration, injection and telangiectases of the anterior and posterior eyelid margins 3. Daily eyelid hygiene (warm compresses, eyelid massage, and eyelid scrubbing) with commercially available pads or using clean washcloth, soaked in warm water +/- dilute shampoo 2. Treatment usually empirical, but cultures should be taken in cases that fail to respond to initial antibiotic therapy b. If marginal corneal infiltrates or corneal vascularization or phlyctenulosis present 6. Consider systemic tetracyclines (doxycycline, minocycline), azithromycin or erythromycin for extensive or persistent disease V. Bacterial resistance from chronic use of topical antibiotic ointments and solutions E. Abnormal tear film, including rapid tear break-up time and increased debris in tear film c. Variable ocular surface signs of chronic blepharitis including marginal infiltrates, keratitis possibly leading to scarring and neovascularization b. Masquerade syndrome (eyelid neoplasm - rare, but should be considered in chronic unilateral blepharitis) B. Daily eyelid hygiene (warm compresses, eyelid massage, and eyelid scrubbing) with commercially available pads or using clean washcloth, soaked in warm water +/- dilute shampoo 2. Artificial tears, if aqueous tear deficiency or lipid-induced tear film instability present 4. Topical corticosteroid for acute exacerbations or if marginal corneal infiltrates or corneal vascularization or phlyctenulosis are present 5. Systemic tetracycline or doxycycline for meibomian gland dysfunction or rosacea (erythromycin in children) 6. Mechanical removal and/or topical ophthalmic ointment to smother the parasites for phthiriasis 8. Effect of Using a Combination of Lid Wipes, Eye Drops, and Omega-3 Supplements on Meibomian Gland Functionality in Patients With Lipid Deficient/Evaporative Dry Eye. The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction. Bacteria infiltrate the conjunctival epithelial layer and sometimes the substantia propria 3. Alterations in ocular surface defense mechanisms or in the ocular flora can lead to clinical infection 4. Transmitted sexually (direct genital-to-hand-to-eye transmission) or from mother to baby during vaginal delivery b. Consider nasal and throat swab if pharyngitis is present or nasolacrimal system evaluation when recurrent conjunctivitis is present 3. Mild conjunctivitis may be self-limiting, but a topical antibiotic speeds clinical improvement and microbiologic remission. Fluoroquinolone (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, or moxifloxacin) iv. If a compromised host, severe purulence, or refractory case, then obtain culture 4. Systemic antibiotics are indicated in Neisseria conjunctivitis, in acute purulent conjunctivitis with pharyngitis, for conjunctivitis-otitis syndrome, and Haemophilus conjunctivitis in children a. Referral to a primary care physician may be necessary if other tissues or organ systems are involved 6. Consider topical erythromycin, bacitracin, gentamicin, tobramycin or a fluoroquinolone for conjunctivitis 6. Irrigation of the eye with normal saline can remove inflammatory material that may contribute to corneal melting 7. If gonococcal conjunctivitis confirmed, treat for chlamydial infection (up to a third of patients may have concomitant Chlamydial infection) a. Use oral doxycycline, or erythromycin, or tetracycline for 1 week, or one-time dose of azithromycin 9. Instructions as to when to return to school or work (usually after at least 24 hours of treatment with topical antibiotics) Additional Resources 1. Infection of the conjunctiva, usually transmitted from the mother to neonate during vaginal delivery 2. Chlamydial conjunctivitis is the most common cause of infectious neonatal conjunctivitis C. Usually bilateral conjunctival injection and discharge 2-5 days after parturition b. Recommend Gram and Giemsa stain and culture of conjunctival scrapings in all cases of neonatal conjunctivitis a. Giemsa stain will demonstrate basophilic, intracytoplasmic inclusion bodies in chlamydia 2. If clinical diagnosis is not confirmed on culture or scrapings, immunofluorescent antibody tests on scrapings can aid in confirming diagnosis 3. Toxic chemical conjunctivitis from silver nitrate or topical antibiotic applied at birth B. Describe patient management in terms of treatment and follow-up for gonococcal conjunctivitis A. Systemic antibiotics if mother has gonorrhea, even if no conjunctivitis present in the neonate C. Topical therapy alone is inadequate and unnecessary if systemic therapy has been given E. Lavage of conjunctival discharge with normal saline to reduce proteases, debris, inflammatory cells which may increase the risk of corneal ulceration F. Describe patient management in terms of treatment and follow-up for chlamydial conjunctivitis A. Topical antibiotic therapy alone is inadequate for treatment of chlamydial infection C. Consult pediatrician for evaluation and management of systemic complications like pneumonitis and otitis media D. Corneal ulceration, perforation, and scarring secondary to gonococcal conjunctivitis B. Precautions to avoid spreading the infection to the fellow eye or other contacts 1. Caregivers should wash hands frequently and wear disposable gloves when cleaning the discharge from the eye C. Ocular infection via direct or indirect contact with infected genital secretions B. May develop mild keratitis with fine epithelial and subepithelial infiltrates and micropannus 5.

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Low birthweight deaths are those resulting from intrauterine growth retardation or preterm birth discount 260mg extra super avana otc. Almost all low birthweight deaths in the neonatal period result from preterm birth order 260 mg extra super avana fast delivery. Epilepsy buy extra super avana 260mg on-line, alcohol use disorders, Alzheimer’s and other dementias, Parkinson’s disease, multiple sclerosis, drug use disorders, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, insomnia (primary), migraine, mental retardation attributable to lead exposure, and other neuropsychiatric disorders. Rheumatic heart disease, hypertensive heart disease, inflammatory heart diseases, and other cardiovascular diseases. Other neoplasms, endocrine disorders, sense organ diseases, genitourinary diseases, skin diseases, musculoskeletal diseases, and oral conditions. Communicable, maternal, perinatal, and 1,551 1,551 6,384 7,935 nutritional conditions A. Note: A blank cell indicates that fewer than 1,000 deaths are attributable to the specific cause. Hepatitis, tropical-cluster diseases, leprosy, dengue, Japanese encephalitis, trachoma, intestinal nematode infections, and other infectious diseases. Low birthweight deaths are those resulting from intrauterine growth retardation or preterm birth. Almost all low birthweight deaths in the neonatal period result from preterm birth. Epilepsy, alcohol use disorders, Alzheimer’s and other dementias, Parkinson’s disease, multiple sclerosis, drug use disorders, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, insomnia (primary), migraine, mental retardation attributable to lead exposure, and other neuropsychiatric disorders. Rheumatic heart disease, hypertensive heart disease, inflammatory heart diseases, and other cardiovascular diseases. Other neoplasms, endocrine disorders, sense organ diseases, genitourinary diseases, skin diseases, musculoskeletal diseases, and oral conditions. Communicable, maternal, perinatal, and 202,202 202,202 228,937 431,139 nutritional conditions A. Note: A blank cell indicates that fewer than 1,000 deaths are attributable to the specific cause. Hepatitis, tropical-cluster diseases, leprosy, dengue, Japanese encephalitis, trachoma, intestinal nematode infections, and other infectious diseases. Low birthweight deaths are those resulting from intrauterine growth retardation or preterm birth. Almost all low birthweight deaths in the neonatal period result from preterm birth. Epilepsy, alcohol use disorders, Alzheimer’s and other dementias, Parkinson’s disease, multiple sclerosis, drug use disorders, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, insomnia (primary), migraine, mental retardation attributable to lead exposure, and other neuropsychiatric disorders. Rheumatic heart disease, hypertensive heart disease, inflammatory heart diseases, and other cardiovascular diseases. Other neoplasms, endocrine disorders, sense organ diseases, genitourinary diseases, skin diseases, musculoskeletal diseases, and oral conditions. Estimates of deaths from specific causes the formats in which the two sets of numbers are presented. To facilitate comparison of the two sets the need for a separate book—Jamison and others (2006)— of findings, annex table 6C. One of the motivations of this chapter is that for their category sepsis or pneumonia. Low birthweight deaths are those resulting from intrauterine growth retardation or preterm neonatal deaths account for fully 37 percent of the world- birth. Almost all low birthwieght deaths in the neonatal period result from preterm birth. Chapter 3 provides an estimate for birth asphyxia and birth trauma deaths for ages zero to wide total of deaths among children under age five. At an earlier stage of this and Regional Burden of Disease Attributable to Selected Major Risk Factors, vol. Lopez, Anthony Rodgers, and work,Nancy Hancock and JiaWang provided valuable inputs Christopher J. Improving Birth Outcomes: Meeting the Challenge in the vided detailed and valuable critical reaction. The term child mortality rate is sometimes used to denote what we Estimates of Intrapartum Stillbirths and Intrapartum-Related Neonatal call the under five mortality rate. New York: further discussed in Fishman and others (2004) and in chapter 4 of this Oxford University Press. Geneva: Global of Disease in 1990: Summary Results, Sensitivity Analysis, and Future Forum for Health Research, Child Health and Nutrition Research Directions. Shahid-Salles, Julian Jamison, and others Global Burden of Disease and Injury Series. Incorporating Deaths Near the Time of Birth Into Estimates of the Global Burden of Disease | 463 Glossary Age-standardized rate An age-standardized rate is a weighted bronchial airflow is usually reversible and between asthma average of the age-specific rates, where the weights are the pro- episodes the flow of air through the airways is usually good. The potential confounding effect of age is wide array of disorders, including diseases of the cardiac mus- removed when comparing age-standardized rates computed cle and of the vascular system supplying the heart, brain, and using the same standard population. The of body structure and function, and domains of activities/par- “optimal” levels of functioning are defined as those levels above ticipation. Health states do not include risk factors, diseases, which further gains would not (in general) be regarded as prognosis or the impact of health states on overall quality of improvements in health. May also include some risk factors or that do not provide meaningful information on underlying prognosis information. Examples include ill-defined High income Category in the World Bank income grouping of primary site of cancer and atherosclerosis. In the first global burden of disease study, Murray and Ideal health Synonymous with full health (q. Incidence rate New cases of disease or injury occurring per Group I causes Major disease and injury cause group used in unit of population, per unit time. These are causes which are Related Health Problems A classification of diseases and characteristically common in populations who have not yet other causes of mortality prepared by the World Health completed the epidemiological transition (q. Life expectancy The average number of years of life expected to be lived by individuals who survive to a specific age. Risk Factor A risk factor is an attribute or exposure which is causally associated with an increased probability of a disease Neonatal period Persons under the age of 28 days are in the or injury. Perinatal deaths Includes stillbirths and neonatal deaths from any cause, including tetanus and congenital malformations. Sensitivity analysis Systematic investigation of the effects on The perinatal period includes the period from 27 weeks of ges- estimates or outcomes of changes in data or parameter inputs tation to 28 days of life. Glossary | 467 Sequelae The medical conditions that can occur among peo- Sullivan’s method A method of calculating health expectan- ple who contract a disease or suffer an injury. Standard Population A population structure that is used to Uncertainty analysis Estimation of range or distribution of provide a constant age or covariate distribution, so that the uncertainty in estimates based on an assessment of the uncer- age- and sex-specific rates within different populations can be tainty or confidence intervals for all data and parameter inputs. The two main classes of interviewed about symptoms and signs experienced by the summary measures are health expectancies (q. Stillbirth Stillbirth refers to the birth of a dead fetus weighing Vital registration A system for the registration of vital events more than 1,000 grams up to 0. Typically, psychological and social influences drive the person to use the addicting substances, and the combination of genetic predisposition and these influences triggers the disease. Chemically depen- dent nurses are susceptible to the scrutiny of boards of authority if their addiction affects the workplace. Therefore, those in author- ity should understand the disease of addiction and use an effective, compassionate approach that will benefit both the addicted nurse and nursing as a whole. Understanding the biological mechanisms that underlie he concept of alcoholism and other drug dependency as addiction can help others recognize and treat the problem with being a disease first surfaced early in the 19th century. The American Nurses Association estimates that 6% to 8% of nurses have alcohol or drug abuse problems serious enough to impair their judgment, meaning that the disease of Defining Addiction addiction profoundly affects the nursing profession. Addiction is defined as the ongoing use of mood-altering sub- The following description of the disease of addiction has stances, such as alcohol and drugs, despite adverse consequences. Characteristics of alcoholism include continuous or peri- phenomenon of craving in some can also be at least partly at- odic impaired control over drinking, preoccupation with alcohol, tributed to these neurophysiologic mechanisms. Under the direct use of alcohol despite adverse consequences, and distortions in influence of the disease, the addict is in an altered state of con- thinking—most notably denial. To the brain, alcoholism and sciousness, one that is now measurable with the newer imaging drug addiction are the same.

They conclude that countries with lower prices or lower market volume had fewer medicines available and also suffered from longer delays in medicine launches (once adjusted for other b c buy extra super avana 260mg with amex, buy generic extra super avana 260 mg line,d variables ) buy extra super avana 260mg free shipping. The alleged reason is that pharmaceutical companies have an interest in delaying product launches in low-price countries until the medicine has been approved for use in high- price countries, thus enabling them to keep prices high in the former. Companies knew that prices in these countries would later become references for other countries, and that those prices, in turn, would be used in other countries as a reference in the future (18-21). By a The delay of a product’s launch is defined here as the number of months that elapse between the product’s global launch and its launch in a specific country (with no distinction made between delays in obtaining the marketing authorization, delays in price setting/reimbursement decisions and the manufacturer’s decision on when to launch). Using an analytical model they estimated that a €1 reduction in German medicine prices would lead to a reduction of between €0. This was made evident in a recent European Commission report that asked companies to indicate which countries they preferred to use for launching new medicines. Companies preferred to initiate their product launches in countries with free prices (United Kingdom, Germany, and Sweden). In contrast, countries with smaller markets, such as Cyprus or Malta, or with lower disposable income, such as Poland, Bulgaria, Lithuania, Latvia, Estonia, Hungary and Romania (23), are mentioned last. Considering the relatively small number of new medicines that actually make any substantial therapeutic contribution over existing ones, such delays in marketing might not necessarily be a bad thing. The countries stated that they combine between two and five criteria to set prices. The second most used method is the cost of existing treatment for the same condition or disease within the same country (8 countries). Some countries use as the comparator the manufacturer’s country of origin (as in the case of Iran and Jordan). However, there are some countries that are commonly used as reference despite not necessarily being in the same region. Then because of its apparent ineffectiveness in containing pharmaceutical expenditure, the system was abandoned. Working Paper 1: External Reference Pricing the United Kingdom, which are chosen due to their low prices, transparency and accessibility of price information. In all of the case study countries, a manufacturer submitting a new product for pricing is obliged to provide the price of the product in the reference countries. Failure to do so or to provide false information could lead to fines and penalties. Regarding the methodology for arriving at the reference price, the most widespread criterion was the minimum price of the set of reference countries (6 countries), followed by the average price (2 countries). The reasons given are either relatively low prices or availability of information. The case studies indicate that it is also becoming popular among developing and transitional countries. Countries differ, as well, in how they enforce the calculated price: some present suppliers with a “take it or leave it” decision, meaning that if they do not accept the price offered, the product will not be approved or reimbursed. At the other extreme are some countries that use the calculated price as a relatively flexible benchmark for negotiating the price. As has been extensively mentioned in the literature, some evidence points to market launch delays in low-price countries. Consequently, countries that in the past were able to obtain relatively lower prices might not be able to do so in the future. Answers to the questionnaires and previous experience of the authors suggest that the reference price does not often become the actual national price, especially in the case of medicines that enjoy a monopolistic position. On the other hand, countries seldom consider potential long-term effects, such as delays in new product launches. However, it must be acknowledgeda that certain countries’ actual objectives may diverge from these. A country might only regulate prices to reduce their pharmaceutical expenditure or to protect domestic industry. This can be interpreted as recognizing investment in research and development in their pricing process. It should also be feasible and affordable in relation to the technical capacities and resources of the country. Another aspect to be considered is whether the mechanism is objective – non discretional – predictable and transparent, as this reduces unnecessary uncertainty to the suppliers. This potentially leads to lower supply prices and fewer delays in marketing a product. Objectivity and transparency are also requisites for ensuring regulators’ accountability and for reducing the risk of corruption and discrimination against certain suppliers. Finally, price regulation mechanisms should take into account the unexpected, long-term effects on the country itself as well as on other countries. It needs to be considered by countries as one of a variety of pricing tools that can be implemented to attain the objectives of universal availability, affordable medicines, equitable access and rational use. For example, price control based on the cost-plus (or cost of production) criterion seeks to determine a price that allows producers to recover production costs and obtain a fair/acceptable profit. Pharmacoeconomic analysis assumes that the price of a medicine should reflect its therapeutic or welfare-added value in relation to existing therapies. It also assumes that new products that do not bring any added value should not get a higher price than existing treatments. To obtain prices similar to – in fact, not higher than - those of a set of countries. To obtain differential - usually lower - prices in relation to those of a set of countries. All the method tries to ensure is that the country does not pay more than other countries do or that it pays less, because the country is not that wealthy. It is, however, difficult to assess whether the resulting prices will be appropriate, efficient or optimal in accordance with any objective criterion. At least one country in the world should use a different method otherwise new products would never be priced and marketed. Medicine regulatory policies are usually a national responsibility, although there are clear trends towards globalisation of some aspects, particularly on efficacy and safety standards for market authorisation and intellectual property rights. Working Paper 1: External Reference Pricing spreads the effects of national price and reimbursement regulations well beyond the regulating country’s own national boundaries. Delaying the launch of new products in countries that try to attain lowest prices, or even not market, especially in small markets where the opportunity cost of the strategy is lower, and countries that are referenced by other countries with larger markets. This pricing strategy, known as discriminant monopolist, can be used only when there is one sole supplier of a medicine. But as companies seek to maximise global profits, wherever possible they could charge a higher single price for the same product in all countries. However, this single price might mean consumers in lower-income countries could not afford to buy the medicine. Imposing a single international price is not a profit-maximising option compared to price discrimination and might not be feasible, anyway. Companies may, therefore, try to apply a second strategy: initially marketing a new product in countries where prices are not regulated or where high prices are common. Launches in lower-price countries may be delayed so as not to influence other countries. This company strategy will not work if the high-price country revises its prices downwards after launch. They can list high prices in reference countries while granting confidential rebates or discounts to thema; i. Companies might also provide a larger number of units than those indicated in the contract in exchange for maintaining the list price. These strategies provide manufacturers with a degree of flexibility in satisfying requests for lower prices from country regulators and payers without compromising prices in other countries that take the former as a reference. Smaller, lower-income countries might end up paying higher transaction prices than the higher income countries taken as reference. The use of pay-backa as a mechanism through which companies agree to return revenue over a predetermined level to public institutions in the form of annual lump-sums. The general discount system used in countries such as Spain (one of the most referenced country) whereby manufacturers have to return 1, 2, or 3% of their annual sales to the Ministry of Health. Regarding marketing delays, the loss of benefits depend on the added value of the medicines concerned. For medicines that make no therapeutic or economic contribution to existing treatments, a delay in launching, or even no launching at all, poses no real loss. But taking into account that “new” medicines do not always provide clear therapeutic advantages, and adverse effects are more likely to appear in the first years of the product life cycle, it is far from obvious that an early launch brings more benefits than costs to a certain country.

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