Committee for Proprietary Medicinal Products (CPMP)
A number of recent applications have led to CPMP discussions concerning the interpretation of superiority, noninferiority and equivalence trials. These issues are covered in ICH E9 (Statistical Principles for Clinical Trials). There is further relevant material in the Step 2 draft of ICH E10 (Choice of Control Group) and in the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. However, the guidelines do not address some specific difficulties that have arisen in practice. In broad terms, these difficulties relate to switching from one design objective to another at the time of analysis. The types of trials in question are those designed to compare a new product with an active comparator. The objective may be to demonstrate: the superiority of the new product the noninferiority of the new product or the equivalence of the two products. When the results of the trial become available, they may suggest an alternative interpretation. Thus the results of a superiority trial may only appear to be sufficient to support noninferiority, while the results of a noninferiority trial may appear to support superiority. Alternatively, the results of an equivalence trial may appear to support a tighter range of equivalence. A satisfactory approach to this subject requires an understanding of confidence intervals and the manner in which they capture the results of the trial and indicate the conclusions that can be drawn from them. Such an understanding also leads to an appreciation of why power calculations are of relatively little interest when a trial is complete. For simplicity, this paper addresses the issues of superiority, noninferiority and equivalence from the perspective of an efficacy trial with a single primary variable. Some comments on other situations are made in Section VI. It is assumed throughout this document that switching the objective of a trial does not lead to any change in the selection or definition of the primary variable. A superiority trial is designed to detect a difference between treatments. The first step of the analysis is usually a test of statistical significance to evaluate whether the results of the trial are consistent with the assumption of there being no difference in the clinical effect of the two treatments. In a trial of good quality, the degree of statistical significance (P value) indicates the probability that the observed difference, or a larger one, could have arisen by chance assuming that no difference really existed. The smaller this probability is, the more implausible is the assumption that there really is no difference between the treatments. Once it is accepted that the assumption of âno differenceâ is untenable, it then becomes important to estimate the size of the difference in order to assess whether the effect is clinically relevant. This has two aspects. First there is the best estimate of the size of the difference between treatments (point estimate). For normally distributed data this is usually taken as the observed difference between the mean values on each. Next, there is the range of values of the true difference that are plausible in the light of the results of the trial (confidence interval). It is clear that this range should not include zero since the possibility of a zero difference has already been rejected as unreasonable. The method of constructing confidence intervals generally ensures that this is so, provided it corresponds to the choice of significance test. Thus the following two statements are usually equivalent: The two-sided 95% confidence interval for the difference between the means excludes zero. The two means are statistically significantly different at the 5% level (P < 0.05) two-sided. The above text addresses the situation where the difference between two mean values is the statistic of interest and a zero difference represents no effect. In practice a number of other summary statistics are used for the evaluation of differences between treatments, for example the odds ratio for proportions or the ratio of geometric means in bio-equivalence studies. (The latter arises from the logarithmic transformation used for bioavailability data.) In such cases the same principles apply but âno differenceâ may be represented by a value other than zero â a value of 1 in both the examples quoted here. In these cases it is the position of the confidence interval for the test statistic relative to this âno differenceâ value that is of interest. When significance tests are carried out in practice, precise numerical values of probabilities are usually quoted, for example P = 0.032, because this is more informative than P < 0.05. This allows judgement to be based more precisely on the extent of the disagreement between the null hypothesis and the observed data rather than on the approximations implied by using cut-off points of 0.05, 0.01 and 0.001. However, confidence intervals have to be associated with a specific probability value (coverage probability) and this is nearly always taken as 95% (0.95). When a difference is statistically significant at a more extreme level, e.g. P = 0.002, the two-sided 95% confidence interval will exclude zero by a wider margin. Figure 1 illustrates these points. Relationship between significance tests and confidence intervals. Whether the observed difference is indeed clinically relevant is a matter of judgement. In contrast to an equivalence or noninferiority trial where clinical relevance is addressed through the prestudy choice of Î (see II.2 and II.3), in a superiority trial clinical relevance requires separate consideration: a statistically significant difference may not be clinically relevant. The difference taken as the basis of the power calculation in a superiority trial cannot be assumed to provide a suitable value. Note that in Figure 1, and throughout the rest of the document, it is assumed that values to the right of zero correspond to a better response on the new treatment so that values to the left are worse, i.e. better on the control treatment. An equivalence trial is designed to confirm the absence of a meaningful difference between treatments. In this case it is more informative to conduct the analysis by means of the calculation and examination of the confidence interval although there are closely related methods using significance test procedures. (See also II.3.) A margin of clinical equivalence (Î) is chosen by defining the largest difference that is clinically acceptable, so that a difference bigger than this would matter in practice. There are well-recognized difficulties associated with this task which will not be discussed in any detail here. If the two treatments are to be declared equivalent, then the two-sided 95% confidence interval â which defines the range of plausible differences between the two treatments â should lie entirely within the interval âÎ to + Î, see Figure 2. There are situations in which the equivalence margins may be chosen asymmetrically with respect to zero. Confidence interval approach to analysis of equivalence trial. In the case of bioequivalence studies a coverage probability of 90% for the confidence interval has become the accepted standard when evaluating whether the average values of the pharmacokinetic parameters of two formulations are sufficiently close. Clinical equivalence trials, with two-sided 95% confidence intervals, may be carried out when conventional bio-equivalence trials are impossible, for example in the case of a generic inhaled or topically applied product. In Phase III drug development, noninferiority trials are more common than equivalence trials. In these we wish to show that a new treatment is no less effective than an existing treatment â it may be more effective or it may have a similar effect. Again a confidence interval approach is the most straightforward way of performing the analysis but now we are only interested in a possible difference in one direction. Hence the two-sided 95% confidence interval should lie entirely to the right of the value âÎ, see Figure 3. Non-inferiority trials are sometimes mistakenly referred to, and designed as, equivalence trials. This distinction is important and can be a source of confusion. Confidence interval approach to analysis of non-inferiority trial. Note also that by using the closely related significance testing procedures referred to in II.2, it is possible to calculate a P value associated with the null hypothesis of inferiority. This is a valuable further aid to assessing the strength of the evidence in favour of noninferiority. It will be assumed throughout this document that two-sided 95% confidence intervals are to be used for all clinical trials whatever their objective. Among other benefits, this preserves consistency between significance testing and subsequent estimation. It is also consistent with the guidance provided in the ICH E9 Note for Guidance. If one-sided intervals are used, then they should be used with a coverage probability of 97.5%. In the special case of bioequivalence studies, two-sided 90% confidence intervals have been established as the norm as recommended, for example, in the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. A conclusion of equivalence or noninferiority clearly depends upon the value of Î chosen as the maximum acceptable difference. It is always possible to choose a value of Î which leads to a conclusion of equivalence or noninferiority if it is chosen after the data have been inspected. Since the choice of Î is generally a difficult one, there is ample room for bias here, however, well intentioned the researcher may be. Plausible arguments may often be advanced for a retrospective choice. In the design of equivalence and noninferiority trials, this reason (amongst others) makes it necessary for the choice of Î, and the reasoning behind the choice, to be set down in advance by the researcher in the study protocol. The corresponding coverage probability for the confidence interval (usually 95%) should also be chosen at this time. (See Section IV.2 for how these requirements apply when objectives are changed.) The question of how to choose an appropriate Î will be addressed in a subsequent CPMP Points to Consider. Pre-definition of a trial as a superiority trial, an equivalence trial or a noninferiority trial is necessary for numerous reasons including the following: to ensure that comparator treatments, doses, patient populations and endpoints are appropriate (see ICH E10) to allow sample size estimates to be based on the correct power calculations to ensure that equivalence and noninferiority criteria are predefined to permit appropriate analysis plans to be described in the protocol to ensure that the trial has sufficient sensitivity to achieve its objectives (see ICH E10) If the objective of a trial is switched from superiority to noninferiority, or vice versa, these aspects may lead to greater difficulty than the interpretation of significance tests and confidence intervals. The only switching which is likely to have any practical relevance is switching between superiority and noninferiority. The place of equivalence trials is so specific that they stand alone. If the 95% confidence interval for the treatment effect not only lies entirely above âÎ but also above zero then there is evidence of superiority in terms of statistical significance at the 5% level (P < 0.05). See Figure 4. In this case it is acceptable to calculate the P value associated with a test of superiority and to evaluate whether this is sufficiently small to reject convincingly the hypothesis of no difference. There is no multiplicity argument that affects this interpretation because, in statistical terms, it corresponds to a simple closed test procedure. Usually this demonstration of a benefit is sufficient on its own, provided the safety profiles of the new agent and the comparator are similar. When there is an increase in adverse events, however, it is important to estimate the size of the effect to evaluate whether it is sufficient in clinical terms to outweigh the adverse effects. Non-inferiority to superiority. There are a number of other factors that might be affected by this changed objective. If the comparator was suitable for a demonstration of noninferiority, then there should be well-controlled data to show that it is an effective treatment. Hence, for proof of efficacy, a clear demonstration of superiority to the comparator in terms of statistical significance should be acceptable. Non-inferiority trials are generally large because of their need to exclude the possibility of a small degree of inferiority of a new agent relative to an active control. However if the new agent is actually superior to control by a small amount, then the power to show its noninferiority is increased. Demonstrating the small amount of superiority to control might in principle require the planning of an even larger trial. When the trial is completed, however, the results provided by the confidence interval supply a concrete assessment of the precision actually achieved, superseding any calculations of power carried out before the trial was undertaken. Since the comparator in a noninferiority trial must be an effective agent, any superiority to that agent should carry the implication of acceptable superiority to no treatment (placebo). For this reason the size of the additional clinical benefit demonstrated is not likely to be relevant to a claim of efficacy except in relation to any increase in adverse effects and hence relative risk/benefit. However, when the proposed licence includes a claim of superiority to the comparator, the size of the additional benefit should be discussed in clinical terms. In a superiority trial the full analysis set, based on the ITT (intention-to-treat) principle, is the analysis set of choice, with appropriate support provided by the PP (per protocol) analysis set. In a noninferiority trial, the full analysis set and the PP analysis set have equal importance and their use should lead to similar conclusions for a robust interpretation. A switch of objective would require this difference of emphasis to be recognized. More details of the relative importance of these two analysis sets in superiority and noninferiority trials can be found in the ICH E9 Note for guidance. A trial to show equivalence or noninferiority must show a high degree of consistency with protocolled plans if it is to be reliable. Deviations from the inclusion criteria, from the intended treatment regimen, from the schedule, manner and precision of taking measurements, and so on, all tend to reduce the sensitivity of a trial and to make a conclusion of âno differenceâ more likely, even when the deviations are of an unsystematic or random nature. The size of the bias associated with these and other departures from the protocol is generally unknown and may render such a trial uninterpretable. Failure to show a difference between two treatments can also arise when both treatments are inefficacious, perhaps as a result of being inappropriately administered. This problem does not affect superiority trials to the same extent because the demonstration of a difference is itself validation of the sensitivity of the trial. The estimate of the size of the effect may however, be similarly affected. For these reasons, switching from noninferiority to superiority is likely to carry with it a greater degree of confidence in the conclusion. Switching the objective of a trial from noninferiority to superiority is feasible provided: The trial has been properly designed and carried out in accordance with the strict requirements of a noninferiority trial. Actual P values for superiority are presented to allow independent assessment of the strength of the evidence. Analysis according to the intention-to-treat principle is given greatest emphasis. If a superiority trial fails to detect a significant difference between treatments, there may be interest in the lesser objective of establishing noninferiority. If the results of the superiority trial are summarized by means of a 95% confidence interval for the treatment difference, the lower end of that confidence interval provides a quantitative estimate of the minimum estimated effect of the new treatment relative to the comparator. When the study protocol an acceptable, margin âÎ for noninferiority, the objective less a noninferiority margin would appear only to make in trials with noninferiority as an However, in any superiority trial where noninferiority may be an acceptable for it is to a noninferiority margin in the protocol in order to the difficulties that can arise from such it is also to design to the possible need to that the study sufficient sensitivity to detect the drug effects of interest (see It is important to that there are of where noninferiority to an active control is to be acceptable as the or evidence of efficacy, and trials are to In trials where there is no noninferiority such a has to be after the and in situations this will not be It is likely that the will have to be after the results have been and there may be little basis for an objective choice of margin. there does not appear to be a statistical multiplicity related to this switch of that does not the difficulties associated with the definition of A number of other issues require A comparator chosen for a demonstration of superiority may not be acceptable for a conclusion of noninferiority. In order for it to be acceptable, it will be necessary to that there are data from good superiority trials consistent evidence that the comparator is an effective treatment with and establishing the size of its effect relative to no treatment. There should also be a basis for that the same degree of efficacy would be in the trial. For example, the patient and the endpoints should be similar. These issues are covered in ICH in the results provided by the confidence interval supply a concrete assessment of the precision actually by a clinical trial, superseding any calculations of power carried out before the trial was undertaken. The position of the lower end of the confidence interval relative to the of noninferiority provides the for noninferiority. In a superiority trial the full analysis set, based on the ITT (intention-to-treat) principle, is the analysis set of choice, with appropriate support provided by the PP (per protocol) analysis set. In a noninferiority trial the full analysis set and the PP analysis set have equal importance and their use should lead to similar conclusions for a robust interpretation. A switch of objective would require this difference of emphasis to be recognized. More details of the relative importance of these two analysis sets in superiority and noninferiority trials can be found in the ICH E9 Note for Guidance. A trial to show equivalence or noninferiority must show a high degree of consistency with protocolled plans if it is to be reliable. Deviations from the inclusion criteria, from the intended treatment regimen, from the schedule, manner and precision of taking measurements, and so on, all tend to reduce the sensitivity of a trial and to make a conclusion of âno differenceâ more likely, even when the deviations are of an unsystematic or random nature. The size of the bias associated with these and other departures from the protocol is generally unknown and may render such a trial uninterpretable. Failure to show a difference between two treatments can also arise when both treatments are inefficacious, perhaps as a result of being inappropriately administered. This problem does not affect superiority trials to the same extent because the demonstration of a difference is itself validation of the sensitivity of the trial. For these reasons, switching from superiority to noninferiority is likely to carry with it a lesser degree of confidence in the It will be necessary to to the sensitivity of the trial by or that the control treatment is its efficacy the trial with trials which demonstrated the efficacy of the control agent in of and of of and data that are at to those in the trials similar results from the full analysis set and PP analysis set. Switching the objective of a trial from superiority to noninferiority may be feasible provided: The noninferiority margin with respect to the control treatment was predefined or can be (The latter is likely to difficult and to be to cases where there is a accepted value for Analysis according to the intention-to-treat principle and PP confidence intervals and P values for the null hypothesis of similar The trial was properly designed and carried out in accordance with the strict requirements of a noninferiority trial (see ICH E9 and The sensitivity of the trial is high to ensure that it is of relevant differences if they There is or evidence that the control treatment is its level of A further related that has arisen in with equivalence and noninferiority trials to the equivalence margins when the trial is complete. that a bioequivalence trial a 90% confidence interval for the relative bioavailability of a new that from to we only that the relative bioavailability lies between the conventional of and because these the predefined equivalence can we that it lies between and The interval based on the data is the appropriate one to Hence, if the changed to this study would have satisfactory There is no question of a selection However, if the trial in a confidence interval from to then a change of equivalence margins to would not be acceptable because of the conclusion that the equivalence margin was chosen to the These apply to the 95% confidence intervals used for clinical equivalence and for noninferiority. The confidence interval based on the results of the trial is always the best summary of the It is the choice of equivalence margin that is subject to This should be chosen on the basis of and not chosen to the This Points to has been from the perspective of an efficacy trial active with a single primary variable. In practice some studies have more than one primary and most studies have respect to switching of these requires separate in the of the specific drug development, separate conclusions superiority or noninferiority for in judgement whether the trial as a has established the superiority or noninferiority of the new treatment will upon the requirements for that clinical and the of results all relevant The covered in these Points to can also be applied to specific safety when these have been as endpoints of a trial to compare active In practice the of switching objectives is not relevant to trials, even where noninferiority to is a valuable i.e. for safety The problem of switching objectives can be by a trial in the that both noninferiority and superiority are of value. In this case all the issues in this document should be addressed In the statistical analysis should be using an appropriate from noninferiority to superiority. The interpretation of superiority trials as noninferiority trials and vice is best by the results as a confidence interval for the difference between the test treatment and control. There is no problem associated with the use of this confidence interval as a basis for of interpretation. For a and trial, there are difficulties with the change from noninferiority to superiority that cannot be addressed by appropriate analysis. However, there are more difficulties associated with the switch from superiority to noninferiority because of the possible need to a basis and on, a margin of equivalence after the and because of the difficulties of noninferiority trials. There are for the design of a superiority trial in which noninferiority might be an acceptable When the results with respect to alternative of the equivalence margins the problem from to switch to wider acceptable that equivalence margins may be in this
Open access
Statistical Methods in Clinical Trials
Health Systems, Economic Evaluations, Quality of Life
The Act No. 221999 on regional government and No. 251999 on the balance of finance between central government and regional government, have vast impact on all aspects of the nation life. The impacts are not only on politic and economic aspects, but they also have logic consequence on the changes of Indonesian education form and system. Based on the rules above, the education process in schools should be independent gradually and will not depend on central government moreover on regional government especially in finance. Consequenly, the quality of school must be improved either in planning or process or outcome aspect. To reach the aimed quality of the schools need a management system that can improve the quality of schools. In this frame, this writing offers the total quality management system as a medium to autonomous education having a certain quality in decentralization era.
In this chapter we discuss pseudorandom generators. Loosely speaking, these are efficient deterministic programs that expand short, randomly selected seeds into much longer âpseudorandomâ bit sequences (see illustration in Figure 3.1). Pseudorandom sequences are defined as computationally indistinguishable from truly random sequences by efficient algorithms. Hence the notion of computational indistinguishability (i.e., indistinguishability by efficient procedures) plays a pivotal role in our discussion. Furthermore, the notion of computational indistinguishability plays a key role also in subsequent chapters, in particular in the discussions of secure encryption, zero-knowledge proofs, and cryptographic protocols. The theory of pseudorandomness is also applied to functions, resulting in the notion of pseudorandom functions, which is a useful tool for many cryptographic applications. In addition to definitions of pseudorandom distributions, pseudorandom generators, and pseudorandom functions, this chapter contains constructions of pseudorandom generators (and pseudorandom functions) based on various types of one-way functions. In particular, very simple and efficient pseudorandom generators are constructed based on the existence of one-way permutations. We highlight the hybrid technique , which plays a central role in many of the proofs. (For the first use and further discussion of this technique, see Section 3.2.3.) Organization . Basic discussions, definitions, and constructions of pseudorandom generators appear in Sections 3.1â3.4: We start with a motivating discussion (Section 3.1), proceed with a general definition of computational indistinguishability (Section 3.2) next present and discuss definitions of pseudorandom generators (Section 3.3), and finally present some simple constructions (Section 3.4). More general constructions are discussed in Section 3.5.
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Olivier Baudron, Pierre-Alain Fouque, David Pointcheval, Jacques Stern ¡ 5 authors
The aim of electronic voting schemes is to provide a set of protocols that allow voters to cast ballots while a group of authorities collect the votes and output the final tally. In this paper we describe a practical multi-candidate election scheme that guarantees privacy of voters, public verifiability, and robustness against a coalition of malicious authorities. Furthermore, we address the problem of receipt-freeness and incoercibility of voters. Our new scheme is based on the Paillier cryptosystem and on some related zero-knowledge proof techniques. The voting schemes are very practical and can be efficiently implemented in a real system.
A proof is concurrent zero-knowledge if it remains zero-knowledge when many copies of the proof are run in an asynchronous environment, such as the Internet. It is known that zero-knowledge is not necessarily preserved in such an environment. Designing concurrent zero-knowledge proofs is a fundamental issue in the study of zero-knowledge since known zero-knowledge protocols cannot be run in a realistic modern computing environment. In this paper we present a concurrent zero-knowledge proof systems for all languages in NP. Currently, the proof system we present is the only known proof system that retains the zero-knowledge property when copies of the proof are allowed to run in an asynchronous environment. Our proof system has $\tilde{O}(\log^2 k)$ rounds (for a security parameter $k$), which is almost optimal, as it is shown by Canetti Kilian Petrank and Rosen that black-box concurrent zero-knowledge requires $\tildeΊ(\log k)$ rounds. Canetti, Goldreich, Goldwasser and Micali introduced the notion of {\em resettable} zero-knowledge, and modified an earlier version of our proof system to obtain the first resettable zero-knowledge proof system. This protocol requires $k^{θ(1)}$ rounds. We note that their technique also applies to our current proof system, yielding a resettable zero-knowledge proof for NP with $\tilde{O}(\log^2 k)$ rounds.
We consider zero knowledge interactive proofs in a richer, more realistic communication environment. In this setting, one may simultaneously engage in many interactive proofs, and these proofs may take place in an asynchronous fashion. It is known that zero-knowledge is not necessarily preserved in such an environment; we show that for a large class of protocols, it cannot be preserved. Any 4 round (computational) zero-knowledge interactive proof (or argument) for a non-trivial language L is not black-box simulatable in the asynchronous setting.
This paper studies the issue of designing an optimal organizational form: design for sub-units' task allocation, decision-making structure, and incentive schemes for organizational members. Depending on the way tasks are allocated between the sub-units, and whether decision-making is centralized or not, organizations face a trade-off between coordination and information. Task allocation by production processes calls for coordination more strongly than the allocation by final products. Centralized decision-making serves for better coordination, whereas decentralization serves for better information. The coordinational benefit under centralization gets bigger as the organization's common uncertainty increases, and this benefit is magnified when the sub-units are functionally divided by production processes. The informational benefit under decentralization gets bigger as the organization's local uncertainty increases, and this benefit is magnified when the sub-units are designed autonomous. Thus, complementarily designed organizations tend to have centralized decision-making structures and fixed salary scheme, whereas less complementarily designed organizations tend to have decentralized decision-making and 'pay for performance' incentive contract.
Teresa GarcĂa-MilĂĄ, Timothy J. Goodspeed, Therese J. McGuire
As part of a process of democratization, many countries spanning Europe, Latin Amertica, Africa, and Asia are reorganizing their governments bydevolving fiscal responsibility and authority to newly empowered regionaland local governments. Although decentralization in each country proceedsdifferently, a common element tends to be an initially heavy relianceon central government grants to fund regional spending. We develop atheoretical model of regional borrowing decisions in which the incentivesfor regional borrowing depend crucially on how the regions expect thefederal system of finance to evolve. We examine the implications of themodel using data on Spanish regions for the period 1984-1995 and findevidence that regions may be borrowing inefficiently in response toincentives imbedded in the Spanish system of fiscal decentralization.
This article studies the effects of political institutions on inflation. In our view, hyperinflation is the manifestation of a tragedy of commons in a divided society with a weak central monetary authority. Economies with fiat money are inherently inflation-prone: the collection of seigniorage through the inflation tax is less conspicuous than other taxes, and the printing of money is essentially costless. In many countries, the control of the money supply is de facto or de jure decentralized. Sets of agents (in various regions or interest groups) can effectively pressure the central government to finance their expenditures. As these interest groups pursue their self-interest, they neglect the welfare effects of the inflation tax on individuals in other groups. These elements combine to imply that countries which rely on the inflation tax to meet the resource demands of competing interest groups will typically experience inefficiently (due to negative spillovers) high inflation.
We model the links between skills and changes in work organization. As the proportion of skilled workers increases, the economy travels through a sequence of organizational equilibria. We show that as the relative supply of skills increases the organization of work becomes more decentralized. Both skilled and unskilled workers become more autonomous and perform a wider range of tasks: decentralization spreads across firms at the expense of the old centralized organization based on a strict division of labor. Moreover, as firms switch to decentralization, their employment structure becomes more homogeneous and wage inequality stops decreasing. These predictions are compared with empirical evidence based on French establishmentâlevel data and we find support for both of them. This suggests that the longâterm increase in the skill level of the workforce may have been one important factor driving the recent introduction of new work practices by a large number of firms.
The paper provides information and analysis in support of the Bank's subnational development strategy (GN-2026). The strategy will guide future Bank operations in support of decentralization to address the complex issues countries are facing in their efforts to promote the socioeconomic development in subnational territories. The document is divided in three sections: the first section provides an overview of the decentralization process in Latin America and the Caribbean and sets the stage for an analysis of the key isuues that need to be addresses by the Bank when supporting the decentralization process in the region; the next chapter discusses the challenges confronted by subnational governments. The development of subnational governments is key to improving well-being. The next section focuses on the structure of intergovernmental relations and concludes that a well-designed structure provides subnational governments with incentives to efficiently allocate resources to the most socially profitable uses. The next chapter discusses the governance issues involved in decentralization, while the next section concentrates on the institucional aspects of the institucional aspects of decentralization and concludes that the Bank should emphasize the need for subnational governments to have sufficient institutional capacity at socially acceptable levels of performance. Finally, the last chapter discusses the variety of issues related to financing subnational governments and recommends that the Bank stress the paramount importance of sufficient sources of financing for ensuing good subnational government performance.
Based on cross-country data for up to 78 countries, this paper shows that fiscal decentralization-the assignment of expenditure and revenue mobilization functions to subnational levels of government-is associated with various indicators of governance, such as corruption, rule of law, and government effectiveness. Unlike previous studies in the decentralization/governance literature, which focus primarily on expenditure-based measures of decentralization, the results reported in this paper show that the relationship between decentralization and governance depends on how subnational expenditures are financed. The higher the share in total subnational revenues of nontax revenues and grants and transfers from higher levels of government, the stronger the association between decentralization and governance.
This paper describes how library operations can be integrated in a cross-platform programming It discusses the organizational and technical issues in planning and designing of macro applications from the technical services workstation. It then describes a variety of technical and public service macro applications. It shows the efficiency and ergonomic benefits of these customized programs. It concludes with an example of how PC-based macro-programs can populate Web-accessible server-side databases with ActiveX technologies. Programming Initiatives Background This article describes how library operations can be integrated, regardless of the systems in use, through what we call the environment. Two keys to a desktop-programmed are the technical services workstation and the macro, a computer program created either through recording series of keystrokes or--far better--through purpose-designed algorithms.(1) While such macros are commonly in use in many libraries within a single system, our article shows how these can be used to link and integrate systems to great functional advantage. At the University of Illinois at Urbana-Champaign (UIUC) we began developing cross-system macros in the context of our migration away from a first-generation system known as LCS/FBR, which had been largely developed in-house and used by a consortium of Illinois libraries.(2) While long-range plans call for moving to a state-of-the-art client/server-centered system, interim arrangements required the implementation of a turnkey telnet-based system, DRA Classic. It quickly became evident that the introduction of new technology would have a profound effect on the library as an organization. Indeed, existing structures and entrenched technologies affected implementation of the system and were in turn highly affected themselves by what was implemented. For that reason, this article looks at the programmed environment not only as a desktop phenomenon, but also as an organizational phenomenon. To have a deep understanding of the real impact desktop computer programming can have in a library, we begin with some organizational and technical issues and how they affected systems and services. Local Organizational Structure The UIUC Library is highly decentralized, made up of some forty-five semi-autonomous departmental libraries. Original cataloging had been decentralized in the mid-1980s; much acquisitions and serials check-in work was also done in the departmental libraries. Serials cataloging and copy cataloging were the respective responsibilities of an Office of the Principal Cataloger unit and of an Automated Services unit. Catalog maintenance was entirely centralized for systems reasons: changes to the consortial catalog could only be performed using hardwired terminals running SuperWylbur or WLN text-editing software. Besides using LCS/FBR, UIUC also maintained a variety of other systems, including IBM for acquisitions accounting and Innopac for serials check-in. All original cataloging was done through OCLC. Hence, multiple input was an overall feature of the configuration. Many parts of the system were not automated; many card files were still in use, especially since retrospective conversion was incomplete. Catalog Maintenance in a Pre-Windows (DOS) Environment UIUC had long grappled with the problem of carrying out catalog maintenance using an inflexible line-editing system. This situation has been documented by Clark and Chan and by Henigman.(3) A variety of computer programs written in BASIC and operating under DOS had been developed to facilitate accuracy and productivity in cataloging maintenance. Essentially, these programs guided inputters in the formatting of data and made possible the interface between the separate LCS and FBR databases. In implementing the new system, however, these programs became obsolete, since SuperWylbur, LCS, and FBR were all being retired. âŚ
The note focuses on the external \n benefits of rural electrification (RE), i.e., improved \n access to communication, education, and economic \n opportunities, in addition to extended health services. It \n outlines key lessons to scaling up RE, namely macroeconomic \n stability, continued government commitments, and \n institutional capacity. However, it also suggests that grid \n extension is not always cost-effective, rather, \n decentralized delivery options, and alternative energy \n sources, such as solar photovoltaic, mini-hydro, and other \n renewable energy sources should be considered. Moreover, \n good practices indicate the need for power sector reform, \n regulatory framework with legal guarantees that utilities \n can operate autonomously, and, financial viability, that is, \n to ensure commercialization, and identify a cost-recovery \n system that takes into account capital investment costs, and \n contributions levels. Strongly emphasized is the involvement \n of local communities in the design, and implementation of \n RE, by setting rural electrification committees, and by \n establishing institutional, and organizational procedures \n for project planning.
This paper analyzes financial dual track in China. We show that the co-existence of a soft-budget track (under centralized financing) and a hard-budget track (under decentralized financing) can be strictly more efficient than the two pure cases. Our argument is as follows. First, a hard budget constraint alone is not sufficient to induce sound firm performances, positive incentives in terms of firms' profitability are needed as well. Second, for an economy such as China where many firms are hopeless money losers, there is pecuniary externality in financing. That is, the total number of firms financed into operation in the economy can affect the profitability of all firms. This paper offers a number of examples of such externality. In such an economy, centralized financing helps internalize the externality, improving firms' profitability, and yet it leads to a soft budget constraint. Under decentralized financing, budget constraint is hard, but firms suffer from low profitability. A financial dual track does better: the existence of the soft-budget sector improves profitability, enhancing the disciplinary effect in the hard-budget sector. Based on this analysis, the paper sheds light on the complementary relation between soft budget constraint syndrome in the state sector and the remarkable growth of the non-state sector in China
Appropriate therapy for amiodarone-induced thyrotoxicosis (AIT) requires a diagnostic precision that may be difficult to achieve (1). Individual cases are rarely straight forward. On June 14, 1999, a 71-yr-old man was hospitalized with a 1-week history of exertional shortness of breath, foot swelling, and feeling poorly. In 1982, he was hospitalized with congestive heart failure and atrial fibrillation, attributed to myocarditis. In 1985, atrial fibrillation recurred and responded to chronic quinidine therapy. In early 1996, quinidine was stopped, followed by paroxysmal and then persistent atrial fibrillation with congestive heart failure (ejection fraction, 20â25%). Amiodarone (200 mg/day) and coumadin were prescribed. In May 1996, his serum TSH was 0.9 ÎźU/mL. In September 1996, he suffered an acute myocardial infarction and underwent angioplasty of stenoses of the left anterior descending and diagonal coronary arteries. He remained in normal sinus rhythm; coumadin was discontinued. Amiodarone was discontinued in 1997 but successfully restarted in March 1998 when atrial fibrillation recurred (TSH 2.3Îź U/mL). Atrial fibrillation recurred and persisted, and amiodarone was discontinued in September 1998, 9 months before admission. On admission (June 1999) he was in atrial fibrillation with a ventricular response of 180. His blood pressure was 90 systolic. He had mild proptosis (left greater than right), lid retraction, neck vein distension, and a slightly enlarged (20â25 g) thyroid. Although bilateral pleural effusions were present on the chest x-ray, interstitial edema was absent. A myocardial infarction was ruled out. His ventricular response was difficult to control despite escalating doses of β-blockers. Laboratory studies are summarized in Table 1. Laboratory data Normal range: T4, 4.5â10.9 Îźg/dL; free T4 index, 4.5â10.9; T3 RIA, 60â180 ng/dL; TSH, 0.5â5.0 ÎźU/mL. Free T4, 0.7â1.5 (ng/dl); TSI, 0â129%; TBII, 0â9.9%; urine iodide, 42â350 Îźg/L. Laboratory data Normal range: T4, 4.5â10.9 Îźg/dL; free T4 index, 4.5â10.9; T3 RIA, 60â180 ng/dL; TSH, 0.5â5.0 ÎźU/mL. Free T4, 0.7â1.5 (ng/dl); TSI, 0â129%; TBII, 0â9.9%; urine iodide, 42â350 Îźg/L. His 20-min 99m pertechnetate uptake was low at 0.19% (normal range, 0.5â3.75). AIT was diagnosed, possibly secondary to Gravesâ disease. He was begun on methimazole (10 mg, po, tid), prednisone (40 mg, po, daily), iopanoic acid (500 mg, po, bid), metoprolol (200 mg, 4 id), and heparin, coumadin, and verapamil in doses up to 120 mg, tid. At the time of discharge his heart rate was 100â120. He was discharged on June 23, 1999, on methimazole (10 mg, po, tid), prednisone (40 mg, po, daily), iopanoic acid (500 mg, po, bid), lopressor (75 mg, 4 id), verapamil (20 mg, tid), lasix (20 mg, po, qd), and coumadin. Prednisone was discontinued after June 24. On July 2, he was in atrial fibrillation with a ventricular response of 104â108; his blood pressure was 90/60. He had lost 12 lbs since his hospital admission and noted less exertional shortness of breath. Mild proptosis, left greater than right, was noted (HuĚrthle exophthalmometer: left, 20 mm; right, 19 mm). TSH-binding inhibitory immunoglobulin titers (TBIIs) had been completed and were weakly positive. Gravesâ disease was considered likely. On July 22, his pulse was 120 (AF). His dyspnea was unchanged, but he had a single episode of angina relieved by nitroglycerine. He noted increased fatigue and heat sensitivity. Methimazole was increased to 20 mg three times daily. Iopanoic acid was continued. On August 6, his radial pulse was 116â120. His ventricular rate on electrocardiogram was 139, increased compared with his previous electrocardiogram, and worsening ST segment depression was present. Although his dyspnea was stable, edema had increased to the mid-calf. His cardiologist considered hospital admission, but careful outpatient observation was the final recommendation. On August 17, thyroidectomy was recommended, in part, based on a serum T4 of 25.9 Îźg/dL, although his serum T3 had fallen to 140 ng/mL. A bilateral thyroidectomy was performed on September 10 without incident or complications. Pathological examination revealed an enlarged thyroid gland (right lobe, 5 Ă 2.5 Ă 1.5 cm; left lobe, 4.5 Ă 2.5 Ă 3 cm), but no weight was recorded. The final pathology report read: âEnlarged thyroid with fibrosis and mild chronic inflammation. There is no evidence of malignancy.â We asked to have the pathological material re-assessed. An addendum was reported: âThe thyroid is diffusely affected with the lesions described as follows. Approximately half of the areas contained islands of dilated thyroid follicles that were lined by attenuated follicular epithelial cells. These islands are separated by areas of collapsed thyroid follicles admixed with fibrosis and prominent vasculature. Nonspecific findings including histocytes and eosinophilic bodies were present. These changes are consistent with those described in amiodarone-associated thyrotoxicosisâ (2). Subsequent hypothyroidism was treated with levothyroxine. In December 1999, he remained in atrial fibrillation, but his ventricular response was 60. Amiodarone is an iodinated benzofuran derivative that is approved for the therapy of life-threatening recurrent ventricular arrhythmias (3) but is also used to treat angina, paroxysmal supraventricular tachycardia, and atrial fibrillation and to maintain normal sinus rhythm after cardioversion for atrial fibrillation (4). Amiodarone contains 75 mg iodine per 200-mg tablet and releasesâź 10% of the iodine as free iodide daily (5). Amiodarone is highly lipophilic and is concentrated in adipose tissue, cardiac and skeletal muscle, as well as the thyroid (6). With prolonged use, amiodarone has an elimination half-life as long as 100 days (6) Amiodarone effects on thyroid function result from iodine release and intrinsic drug properties (7). Pharmacologic iodide administration to euthyroid individuals with intrinsically normal thyroid glands results in transient inhibition of thyroid hormone synthesis and release, decreased thyroidal iodide trapping, and enhanced T4 (3,3â˛,5,5Ⲡtetraiodothyronine) rather than T3 (3,3â˛,5 triiodothyronine) production by the thyroid, so-called autoregulatory functions (8). The net effect is a slight serum TSH increase that occasionally exceeds the normal range (9, 10). With chronically higher iodide intake, the prevalence of Hashimotoâs thyroiditis increases in genetically susceptible human and animal populations (11â13). In addition, pharmacologic iodide administration may precipitate hypothyroidism in patients with Hashimotoâs thyroiditis (14). Approximately 6% of patients receiving amiodarone develop iodine-induced hypothyroidism; the prevalence is higher in areas of iodine sufficiency and lower in iodine-deficient areas (15). Hypothyroidism may develop as soon as 2 weeks and as long as 39 weeks after starting amiodarone (7). Iodide supplementation in iodine-deficient endemic goiter populations triggers epidemics of hyperthyroidism in a minority of the population, the so-called Jod-Basedow phenomenon (16). Eighty-five percent of these hyperthyroid patients have nodular goiters. Autonomous areas within the nodular thyroid gland overproduce thyroid hormone when exposed to excess substrate (iodide) but are relatively impervious to the autoregulatory effects of iodine (17). However, some hyperthyroid patients have diffuse thyroidal uptake suggestive of Gravesâ disease (18). As in the Hashimotoâs thyroiditis example above, excess iodide seems to trigger or facilitate an immunological attack on the thyroid (19). Additionally, borderline iodine-deficient patients with Gravesâ disease in remission commonly relapse after adding 500 Îźg iodide daily (20), an amount comparable with the daily iodide intake in many iodide-sufficient areas. Pharmacologic doses of iodide may also precipitate hyperthyroidism in euthyroid individuals with nodular thyroid glands in iodine-sufficient regions (21). Case reports (22) and the amiodarone experience suggest that iodine excess may also precipitate Gravesâ hyperthyroidism in iodine-sufficient areas, but this conclusion is uncertain. Amiodarone also has powerful effects on thyroid hormone metabolism (7). Amiodarone inhibits the peripheral conversion of T4 to T3 and may inhibit T3 receptor binding and action (23â25). In euthyroid individuals, T4 and free T4 concentrations increase by 42% due to decreased T4 clearance (7). Reverse T3 (3,3â˛5Ⲡtriiodothyronine) concentration rises by 172%. Efficacy and toxicity of amiodarone may be proportional to reverse T3 concentration (26). Serum T3 concentrations initially decline by 20â25%, subsequently an average 16% below baseline, but may be frankly low in some patients (7, 27). Serum TSH rises, occasionally out of the normal range, but with chronic administration generally remains in the normal to high normal range. It is uncertain whether TSH elevation in the 10â20 ÎźU/mL range represents peripheral subclinical hypothyroidism or is a pituitary specific effect of amiodarone. Some authors accept subnormal serum TSH concentrations with normal T3 concentrations as compatible with the euthyroid state. However, I interpret these findings as evidence of amiodarone-induced subclinical hyperthyroidism. The 24-h radioiodine uptake decreases to low levels (<4%) in euthyroid individuals taking amiodarone (28). This is to be expected because 15 mg inorganic iodide daily, after a loading dose of 30 mg, decreases mean 24-h radioiodine uptake to less than 2% after 12 days (10). When added to antithyroid drugs, amiodarone facilitates the treatment of severe hyperthyroidism (29), by inhibiting T4 to T3 conversion, thyroid hormone release, and possibly T3 receptor binding and action. Unfortunately, 3% of patients exposed to amiodarone develop hyperthyroidism (30), with a higher prevalence in iodine-deficient regions (15). AIT may have a male predominance (31), reflecting the higher cardiovascular disease prevalence in men. Hyperthyroidism may occur 4 months to 3 yr after initiating therapy or after drug withdrawal (28) and is not related to cumulative drug dosage (7). Knowledge of three distinct types of AIT is required to understand this case (1, 30). Amiodarone-induced toxic nodular goiter, a form of iodine-induced thyrotoxicosis, was described in Europe where large nodular goiters are more prevalent than in the United States. Despite antithyroid drug therapy, some patients demonstrated refractory hyperthyroidism (28). The addition of perchlorate to antithyroid drugs decreased the time to euthyroidism in uncontrolled trials (32, 33). Perchlorate inhibits the thyroidal iodide trap and permits the back diffusion of free (nonorganified) iodide from the thyroid gland, so-called perchlorate âdischargeâ (34). Doses of perchlorate higher than 1.5 g per day may cause aplastic anemia, whereas doses of 1 g per day used in these studies are apparently safe. Emergency thyroidectomy was required in some patients, a courageous approach in these critically ill patients. The mechanism of refractory hyperthyroidism is uncertain. Thyroidal iodine stores are much higher in hyperthyroid compared with euthyroid patients receiving amiodarone (34A ). The expanded iodide pool is invoked to explain refractory hyperthyroidism, because antithyroid drugs prevent thyroid hormone synthesis but not hormone release. However, pharmacologic iodide inhibits thyroid hormone release from autonomous nodular thyroid glands when new hormone production is blocked by antithyroid drugs (35). Although amiodarone was often discontinued at the onset of thyrotoxicosis, a continued high iodide environment persisted due to its long half-life. A second group of patients treated with amiodarone developed Gravesâ hyperthyroidism characterized by diffuse thyroid enlargement, a prolonged course, and the presence of thyroid autoantibodies (30). T-cell populations specific for Gravesâ disease have been demonstated as well (36). Most authors infer that âlatentâ Gravesâ disease was made overt by an iodine-stimulated immune attack on the thyroid. Proof of this assumption requires specific markers for genetic Gravesâ disease. Toxic nodular goiter and Gravesâ disease comprise Type I AIT, hyperthyroidism in patients with preexisting or âlatentâ thyroid disease. Type II AIT is a form of âdestructive thyroiditisâ (37), which develops in patients with baseline normal thyroid glands. Hyperthyroidism is due to release of stored thyroid hormone. The thyroid is usually nontender, but pain may occur. The sedimentation rate is generally within normal limits. Amiodarone, its metabolites, and intrathyroidal iodide have all been implicated in cellular toxicity, however, amiodarone is also toxic to cells that do not incorporate iodine (38, 39). Hyperthyroidism lasts for 1â3 months, until thyroid hormone stores are depleted, but resolves more quickly after glucocorticoid therapy. Transient and rarely permanent hypothyroidism may ensue, but the prevalence is uncertain (37). Subacute lymphocytic thyroiditis (âsilent thyroiditisâ) and subacute granulomatous thyroiditis (âpainful subacute thyroiditisâ, de Quervainâs thyroiditis) are worthy of study as other examples of destructive thyroiditis that follow a similar course (40). Hyperthyroidism with a nil 24-h radioiodine uptake is often followed by hypothyroidism. Subacute lymphocytic thyroiditis is an autoimmune disorder with a predilection for the postpartum period (postpartum thyroiditis). Thyroid autoantibodies are generally present, diffuse lymphocytic infiltration is found on biopsy, and permanent hypothyroidism occurs in a significant minority of patients. Subacute granulomatous thyroiditis is characterized by intense thyroid pain, a very high sedimentation rate, severe thyroid follicle disruption, and multinucleate giant cells. Permanent hypothyroidism is rare (41). Amiodarone-induced destructive thyroiditis seems not to be an autoimmune disorder because antithyroid antibodies are generally absent. Hypothyroidism, when it occurs, is usually transient. Although limited numbers of such thyroids have been examined, follicular disruption, zones of fibrosis, and mild inflammatory changes are usually present, but dense lymphocytic infiltration and multinucleated giant cells are usually absent (2, 38). Type II AIT was diagnosed on histological examination of our patientâs thyroid gland; hyperplastic changes of Gravesâ disease were absent. Type II is the most common variety of AIT in our clinic. Type I AIT is more common in Europe; the geographic differences likely reflect the higher iodine intake in the United States. Many patients with AIT II demonstrate minimal transient hyperthyroidism, diagnosed by fully suppressed TSH alone (personal observation). Permanent hypothyroidism is rare, even when amiodarone is continued (personal observation). Some episodes of Type II AIT may represent subacute lymphocytic thyroiditis precipitated by amiodarone (42). Occasional patients develop repeated cycles of hypothyroidism, followed by hyperthyroidism (43) Appropriate therapy of AIT requires a clear distinction between Type I and Type II AIT. How can this be accomplished (Table 2)? AIT-differential diagnosis and therapy Based on European experience (see text). AIT-differential diagnosis and therapy Based on European experience (see text). Given the high iodine content of amiodarone, a nil 24-h radioiodine uptake might be expected in all patients taking this drug. However, detectable or normal 24-h radioiodine uptake is found in 80% of patients with amiodarone-associated hypothyroidism in Europe (44). Furthermore, in Europe type I AIT is accompanied by low, normal, or high 24-h radioiodine uptake, a possible consequence of baseline borderline low iodide intake (45, 46). The radioiodine uptake is near zero in all patients with Type II AIT. A normal or high radioiodine uptake effectively excludes Type II AIT, however, a nil uptake cannot distinguish between Type I or Type II. All patients with Type I and Type II AIT seen in our Thyroid Clinic have a near nil uptake. Systemic radiodine studies of Type I AIT are needed in the United States. If confirmed, our observations suggest that 24-h radioiodine uptakes are superfluous in AIT in the United States. A low (0.19%) 20-min 99m pertechnetate uptake was measured in our patient. In contrast to the 24-h radioiodine uptake, this test can be performed while receiving antithyroid drugs, allowing therapy to begin immediately. Thyroid ultrasonography may allow us to discriminate between Type I and Type II AIT. Thyroid nodules are easily diagnosed by ultrasound and in their toxic nodular goiter is effectively However, destructive thyroiditis may with a nodular thyroid Thyroid ultrasound with can thyroid blood Type I AIT with Gravesâ disease has normal or increased blood whereas Type II AIT a with decreased In patients with Type I from Type II AIT Many studies on thyroid nodules but not When ultrasonography in patients with AIT, thyroid gland studies be Thyroid as the but experience in iodine-sufficient areas such as the United be before it can be fully other studies antibodies are present in at of patients with Gravesâ hyperthyroidism and are generally absent in AIT II. antibodies and are considered specific for Gravesâ disease. When thyroid autoantibodies are no can be were found in our Gravesâ disease. Serum is a that and T-cell is in Type II AIT and normal to at most slightly in Type in Type II AIT are and in Type I AIT I are However, have seen low concentrations in patients with Type II AIT, reflecting of was not measured in our patient. T3 is a of Gravesâ hyperthyroidism. The of serum T3 to T4 concentration is a that can be in Gravesâ hyperthyroidism from destructive when radioiodine uptakes cannot be In of patients with Gravesâ hyperthyroidism had a T3 to T4 greater than whereas of those with âdestructive thyroiditisâ and 6% of euthyroid individuals were in this range This has not been in AIT. A low is to be because amiodarone inhibits T4 to T3 conversion, however, a high AIT patients receiving amiodarone have a mean T3 to T4 of whereas AIT patients have a mean of 12 (7). of I and II AIT have not been patientâs T3 to T4 of the diagnosis of Gravesâ hyperthyroidism. Type I AIT with Gravesâ disease and Type II AIT present with a normal to diffusely enlarged thyroid. or a thyroid Gravesâ disease. However, pharmacologic doses of iodide mg/day) thyroidal blood in Gravesâ disease and a may within days of iodide administration (personal In our thyroid was to Gravesâ hyperthyroidism was diagnosed based on findings and TBII, although this to be We not an ultrasound or in our studies that in might have been The of is uncertain because pathological changes in Type II AIT are often Table 2 the therapy of I and II AIT. of toxic nodular goiter methimazole or perchlorate may be With prolonged hyperthyroidism, or continued amiodarone be considered The of radioiodine therapy in patients with normal or high 24-h radioiodine uptake is uncertain. Type I AIT due to Gravesâ disease is treated in a similar 12 patients with Type I AIT (10 with toxic nodular goiters and 2 with Gravesâ were treated with a of methimazole and perchlorate All normal free T3 concentrations by 4 weeks A diagnosis of Gravesâ hyperthyroidism was made in our patient. Methimazole was and iopanoic acid was added to hormone release and inhibit T4 to T3 conversion, functions also by amiodarone. The 24-h urine iodide was perchlorate was not It is to amiodarone for weeks after starting antithyroid drugs in Type I AIT patients, but this is of Although amiodarone serum half-life is the of T4 to T3 inhibition after drug is Hyperthyroidism in Type II AIT is but some patients critically ill with cardiovascular therapy the hyperthyroidism of Type II AIT and may be treated 12 Type II AIT patients with prednisone (40 mg/day) for with a 3 Free T3 and after an average of and In our many patients euthyroid after weeks of However, hyperthyroidism then prednisone be A response to glucocorticoid therapy is an in difficult a diagnosis seems therapy at Type I and Type II AIT including when from and antibodies often days to weeks to was ill on admission. Amiodarone had been discontinued. Although Gravesâ disease was the diagnosis based on his methimazole and iopanoic were all prescribed. When the results prednisone was discontinued. The was attributed to iopanoic acid but may have been due to prednisone therapy. In a course of prednisone therapy have been and might have been A for was made when the was When for the was but the and his a The diagnosis was in and therapy with antithyroid drugs might have been In more with a diagnostic approach might have been amiodarone be discontinued in all cases of When the cardiac amiodarone in AIT but therapy for weeks after starting antithyroid Many authors amiodarone in Type II AIT, however, this is the diagnosis is cases of Type II are had been amiodarone for 9 months, Type II thyroid before starting The drug is usually begun in an or by without for thyroid disease. However, a approach be to a history of autoimmune thyroid disease and serum TSH and antithyroid These studies might be in amiodarone-associated hypothyroidism and possibly allow of âlatentâ Gravesâ disease. Thyroid ultrasound patients with nodular thyroid glands at for AIT but its might be more in Europe where AIT I is more AIT to our Although clear are diagnosis and therapy for an may be studies in the United and in AIT are or 99m pertechnetate uptake is but may be superfluous in the United States. Although in some this case the that with AIT.
Invasive exotic or alien species cause enormous damage to the natural environment. Indeed, 49% of all imperiled species in the United States are threatened in part by alien species (Wilcove et al. 1998). The toll may be even higher: Additional plant species have been harmed by alien species but have not yet been designated as imperiled (e.g., the American chestnut, Fraser fir, American elm, flowering dogwood). Losses in the agriculture, forestry, and other sectors of the US economy and control costs associated with invasive alien species total $137 billion annually. Approximately $80 billion of that amount is associated with alien plants, insects, and disease pathogens subject to phytosanitary regulations (Pimentel et al. 1999), which are the subject of this article. Because attempts to eradicate established invasive alien species have met with little success, scientists recommend that governments put the highest priority on preventing introduction of such species. This article examines US policies governing the structure and implementation of prevention programs aimed at alien plants and those insects and disease pathogens considered to be plant pests. Whereas many invasive plants have been imported deliberately, insects and fungal pathogens usually hitch a ride with imported cargo. As Chris Bright noted during a presentation at the Worldwatch Institute on 8 October 1998, international trade âleaksâ exotic species. Many others also have predicted that severe damage would follow introduction of insects and fungal pathogens from forests in Europe, Mexico, Asia, or other regions that trade heavily with the United States (Forest Service 1991, 1998, Campbell and Schlarbaum 1994, Niemela and Mattson 1996, APHIS 1998c, 1998d). Some types of imports are particularly likely to transport hitchhikers. Live plants imported for horticultural use, for example, have been called a âuniquely efficient pest introduction pathwayâ (Regelbrugge 1998). Between 45% and 86% of various categories of pests introduced to California in recent decades came in on horticultural imports (OTA 1993). Among forest pests that were most likely introduced on imported live plants are dogwood anthracnose (Discula destructiva Redlin) (Campbell and Schlarbaum1994), Melampsora fungus on larch and poplar, and pine pitch canker (Fusarium subglutinans f. sp. pini) on Monterrey pine (Pinus radiata) (Haleamau 1998). Like live plants, âgreenâ woodâraw or unprocessed woodâis a high-risk import. Crates, pallets, spools for cable, and other packaging are often made from low-quality, pest-damaged wood. When not in use, these items are usually piled in the open air, thus facilitating pests' establishment (APHIS 1998d). As US imports have grownâby more than 50% just since 1990 (GAO 1997)âso too has the quantity of solid wood packaging in which they are shipped, thus presenting more opportunities for exotic species to travel to North America. Another wood pathway for pests is through imported logs, unprocessed lumber, and wood chips. Those US imports once came almost exclusively from Canada, which is a low-risk source because forests in these two nations are contiguous. However, beginning in the 1990s, US wood processors have imported increasing quantities of green wood from geographically separate areas that harbor pests inimical to US forests. Although Canada still supplies more than 70% of US wood imports, Mexico supplies more than 3%, China more than 2%, Chile nearly 2%, and New Zealand about 0.6%; the remainder comes from tropical countries. These imports are expected to increase in the future now that a court injunction limiting imports has been lifted. Some knowledgeable observers, including scientists working with horticultural and forest pests (La Fage and Williams 1979, Niemela and Mattson 1996), as well as the National Plant Board (National Plant Board 1999), have concluded that the phytosanitary safeguards set out by the US Department of Agriculture (USDA) are inadequate to prevent introductions at current trade levels. According to the National Plant Board, âRecent breaches of the APHIS-PPQ [Animal and Plant Health Inspection Service, Plant Protection and Quarantine] safeguarding system that led to entry of dangerous invasive plant pests in the U.S. have raised concerns that current organizational policies and procedures are inadequate to execute Agency functionsâŚ. Clearly, the current safeguarding system cannot meet the changes thrust upon it by rapidly transforming global circumstancesâ (National Plant Board 1999, p. 40). Yet with imports rising, the danger of alien organisms reaching America is increasing, and phytosanitary controls would have to be tightened commensurately to ensure the same level of protection. APHIS has begun to strengthen its regulations for wood packing (APHIS 1998e, 1999a) and lumber from Mexico (APHIS 1999b); both of these rulemakings are still in process. Nonetheless, it has fought in court against scientists who argue that regulations should be strengthened also for logs and lumber from New Zealand and Chile; it has rejected similar pleas from the Oregon Department of Agriculture for regulation strengthening. Moreover, the USDA has relaxed controls for certain horticultural imports. To be âscience based,â a phytosanitary program should reflect the serious threat posed by exotic species to agriculture, horticulture, and forestry, and to the myriad natural ecosystems and biotic communities found from Alaska to Florida and from Maine to Hawaii. It should also reflect practical realities. First, ecologists realize that their knowledge of the millions of insects, fungi, and disease pathogens living in the habitats of US trading partners is limited. Indeed, probably less than 5% of the Earth's fungi have even been named by science; fewer still have been studied enough to determine their ecological role. Scientists know more about exotic insects and plants, but even among these groups are tens of thousands of species that have not been well studied. Given these large information gaps, it may well be impossible for scientists to predict which foreign species might cause devastating damage if introduced to a new ecosystem. Second, biological invasions are usually irreversible, given current scientific knowledge, limited funding, and burgeoning pest problems. In other words, it is far easierâand less expensiveâto prevent an invasion than to combat one. It follows that a sound phytosanitary program should seek to bar entry to all exotic organisms except those that have been evaluated and determined to be very unlikely to be invasive. Two slogans express this goal: âIf in doubt, keep it outâ and âGuilty until proven innocent.â To put this objective into practice, the responsible government agencyâUSDA's APHISâcould combine technological treatments with stringent regulatory requirements that importers act to minimize the likelihood that living, unapproved insects, fungal pathogens, viruses, or weeds will hitchhike to this country on imported goods. This approach obviates several problems. First, it reduces the burden on port inspectors, who would otherwise have to search millions of shipments for tiny, even microscopic, organisms. Second, it reduces the risk that an erroneous assessment of the potential impacts of an organism will result in a decision to allow entry of a species that turns out to be highly damaging. An appropriately serious phytosanitary program should also seek out and utilize all available and emerging information on pests, pathways, and exclusion or mitigation technologies, and rapidly adapt regulations to reflect that new information. However, USDA officials have rejected the âIf in doubt, keep it outâ policy (Isi Siddiqui [US Deputy Under Secretary of Agriculture], personal communication, 1998), finding it incompatible with trade promotion; APHIS is now trying to âbalanceâ protection and trade promotion. Thus, rising trade volume is not the sole reason that the threat of introduction of harmful bioinvaders is growing. Although USDA policy that proves ineffective can be changed through domestic political channels, pro-trade policies now have the force of international law through US adherence to global trade rules enforced by the World Trade Organization (WTO). Thus, if these policies do result in too high a risk of introduction of pests, international treaties adopted by 135 countries must be changedâa daunting challenge. Phytosanitary measures are no longer adopted unilaterally in response to a country's perception of risk. Phytosanitary safeguards are now subject to international standards and review. In 1994 more than 100 countries concluded the Uruguay Round of the General Agreement on Tariffs and Trade by forming the World Trade Organization, which sets the rules for international trade. To prevent member nations from using phytosanitary safeguards to protect domestic agricultural producers from foreign competition, the signatories simultaneously adopted the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS agreement; see www.wto.org). In November 1997, the 46-year-old International Plant Protection Convention (IPPC), which was formed to control plant pests and diseases and prevent their spread across national borders, was revised to bring it into compliance with the SPS agreement. (The IPPC revisions have not yet come into force, however, because too few nations have ratified the changes.) Under the SPS agreement and revised IPPC, countries may impose trade restrictions to the extent necessary to protect human, animal, or plant healthâincluding wild fauna and floraâas long as they apply the same standards for protection across the board, domestically as well as internationally. Phytosanitary measures must be based on scientific principles and supported by scientific evidence, as documented in a risk assessment. When scientific information is insufficient to meet the requirements for risk assessment laid out in the SPS agreement, a country may adopt a provisional regulation while seeking more information. Taking into account available scientific evidence, the risk assessment should address processing or production methods; inspection and sampling methods; prevalence of the target organismâor the existence of pest- or disease-free areasâin the exporting and importing countries; ecological and environmental conditions; and quarantine or treatment measures that could control any pest that is introduced. A risk assessment should also take into consideration the potential damages from introduction of a pest or disease (such as losses in production or sales and the cost of control or eradication) and the cost-effectiveness of alternative approaches to limiting risks. The SPS agreement states that phytosanitary regulations should not be more restrictive than necessary to achieve a country's chosen level of protectionâwhich could be set at zero riskâand that the process of their promulgation must be transparent. Finally, the SPS agreement grants developing countries more time to comply with international phytosanitary standards and calls on WTO member countries to give them technical assistance. Countries that believe their exports have been discriminated against may challenge the importing country's phytosanitary protections as nontariff barriers to trade; if the challenger wins its case, the importer must either revise the phytosanitary regulations or pay a penalty. The penalty can be substantial: For example, after the European Communities (EC) refused to accept a WTO Appellate Body ruling allowing entry of US beef from cattle treated with growth hormones, the United States imposed a $116.8 million tariff on various European food exports (Williams 1999). The SPS agreement is only now being interpretedâoften through official decisions of WTO dispute settlement bodiesâthus many questions remain to be answered about what the agreement allows. USDA is wrestling also with questions about how it will apply certain provisions. For example, what level of protection should the United States strive to maintain? Which agencies, in addition to APHIS, should weigh in on this policy? Because any pests introduced as a result of APHIS policies will affect everyone in the United States, as well as the environment, all of the issues surrounding the SPS agreement should be the subject of broad discussion. Two topics in particularâdetermination of an appropriate level of protection and âquarantine pestsââshould be part of that discussion. As mentioned above, each country has the right to set its own level of protection, even if that level is zero risk. However, a country must consistently apply comparable levels of protection in comparable situations; a further limitation to this right to determine an appropriate level of protection, according to the WTO Appellate Body, is that the country is obligated to demonstrate a scientific justification for the selected level of risk (Victor 1999). The consistency requirement exposes any phytosanitary safeguard to comparison with other domestic or international statutes aimed at managing a comparable risk orâimportantlyâto comparison with the absence of such statutes. A gap in the protection provided by these statutes could be cited as proof that a stringent phytosanitary regulation is inconsistent with existing standards. Indeed, the Appellate Body ruled against Australia when that country banned imports of salmon largely because the sanitary measure for salmon imports was more stringent than that for other fish imports judgedâby the WTO dispute panelâto pose an equal or greater risk (WTO AB-1998-5). For stringent phytosanitary safeguards to survive a challenge under the SPS agreement, then, countries must close any loopholes in regulations governing comparable situations. Of course, tightening these statutes takes time and may prove difficult because of political pressures. Until these steps are taken, however, differences in a country's approach to various risks to health and to the environment might be challenged as or are to be (WTO The SPS dispute have also ruled that a country's of its level of risk be supported by a risk that assessment must be even scientists have little to predict which foreign species may prove when introduced to a new environment. In the from US the dispute supported by the Appellate Body, noted that the scientific on which the European Communities based their level of risk were in the of they not as the Appellate Body they the potential of the at levels found more or when the are for growth in (WTO p. this level of to a risk assessment for potential plant pests might restrictions on imports by both that a fungus has the potential to damage in the importing country and that the fungus might be on an imported The risk assessment would probably have to address each species or to logs for the Appellate Body that is not is a of A risk the the of or (WTO p. Although the Appellate Body imposed it that the not have to be must it prove that the damage would any (WTO AB-1998-5). Given current levels of scientific knowledge and funding, can APHIS be expected to the likelihood or that any of the of insects, fungi, or plant of which could hitch a ride on any from any of US trading any of the agricultural or natural ecosystems of the United Moreover, the Appellate Body not the that many other potential pests cannot be evaluated at because they are either to or or in their APHIS can apply phytosanitary an organism for control must have been designated a âquarantine must be based on a risk the in and scientific just In practice, for example, APHIS might well be to predict that certain insects on imports of pose a threat to in do scientists have information to how those insects might in natural to the potential for invasion by other species of or pathogens on the same It is that APHIS can these the time to risk that imports of to pose severe pest risks can for several APHIS can the process and impose new For example, APHIS in that it considered solid wood packing to be of the pest of all wood imports (APHIS it its risk assessment regulations only in October APHIS the in The only a country can the to the and its with such is through of provisional measures under the of article In ruling on the US challenge regulations on imports of and the Appellate Body that a measure cannot as provisional the country is seeking the information and will the provisional measure a (Victor 1999). The is in the many in which APHIS with it must either to allow the organism with invasive potential into the it will not prove to impose a provisional on its and to trying to the standards of the SPS agreement. The to for the of information on species may well be to on of it has been determined that pests may be introduced a certain of or its country of APHIS should to the available to that or as as to insects, fungi, and the SPS agreement allow a country to adopt such an safeguard on the of a risk assessment that examines a of pests that might be associated with that and not Although pathway regulation has not yet been at in a the on in the of the agreement and in Appellate Body that such an approach would be found when an organism has been designated a âquarantine the still phytosanitary to ensure that their phytosanitary requirements cause the to trade. In other words, of the most measure to against or a country must accept risk of that and adopt those measures that a level of protection. For example, in the of logs and lumber imported from New Zealand and APHIS the less of alternative measures in to the burden on APHIS with that treatments would be more than with in preventing pest its of by that is to the agricultural and its forest from exotic plant pests, but it also has the ensure international only to the to meet plant protection of plant pest risk to a To this would be considered trade restrictions under and subject to challenge by other trading partners in the World Trade (APHIS p. The SPS agreement and revised IPPC the right of the United States to protect from introduction of the thousands of species of pests and weeds that are natural ecosystems in the country insects, see Niemela and Mattson 1996, APHIS for plants, see and the Plant at more organisms to these species into the country several The the species to the new imports may a in an not and the imported organisms may a that is to control than established from the New Zealand see et al. 1999). the SPS agreement and IPPC allow a country to phytosanitary barriers for pests in the country only when the species is not and an official control program the or when the introduced organism from its in the United States in a that the potential to cause greater which as an control will affect the types and of established pests and weeds against which APHIS can protect US ecosystems from imports. however, the to control programs for more than a few species. A of could for phytosanitary controls at US borders, provided that regulatory and programs are considered control Given the that could result from allowing introductions of established it would be appropriate to all in the of which of are to be official control As noted above, the SPS agreement also governments to of an established pest when the new in from in the However, phytosanitary have been to in their attempts to determine such that can have serious the spread of of disease by several fungi in the which when phytosanitary imports of logs, based on their that the disease only that was in their countries. APHIS policies and procedures to be which may the threat from of the SPS agreement. For example, according to the National Plant Board, APHIS-PPQ risk assessment process not the in the it on which or are Many of the process are (National Plant Board 1999). In response to this APHIS has a of its risk assessment October 1999, the a in the seeking on the and on November 1999, it a the an in risk on a process and noted in APHIS the for with the process to ensure that no is also noted that APHIS too on the of an introduction and too little on the of such an introduction 1999). APHIS is also a to and existing international standards and the current of the APHIS to a with of changes in ensure and The SPS agreement was almost by in trade and not in the new of invasion Under the it is not that the SPS agreement phytosanitary safeguards and the danger of harmful The danger from to heavily on risk when the are the priority to trade protection from biological invasion not the of species and biological subject to its on and a few species than on preventing any introductions the of the differences in risk of associated with shipments from as to producers A for American scientists to the issues raised in this article and to for changes in policies that to pest exclusion In US an Invasive and it with developing for US programs to prevent and to The Invasive should the SPS agreement and IPPC allow countries to adopt phytosanitary programs to the structure in In the APHIS can its pest exclusion program the imposed by the SPS agreement and IPPC by zero which it should appropriate level of protection. Although this new would not âIf in doubt, keep it outâ or âGuilty until proven as the in it would the to be as as when for example, which organisms should be considered âquarantine As above, APHIS is to its risk assessment assessment may be an appropriate for to set for search and on pests, but the process is too and too to to a scientific for an exclusion
After the 1988 Constitution, as a consequence of an unplanned decentralization process, the increase of social expenditures by local governments has contributed to aggravate the financial situation of these governments. This aggravation poses a serious problem to the financing of social policies, thus threatening their future implementation and implying the worsening of social inequalities. This paper discusses the decentralization process of public policies and the federative equilibrium in Brazil.
Of the various brewing biological crises of our time, the issues of declining biodiversity and emerging disease are among the most complex and far-reaching. In many respects they are also different sides of the same coin, a perspective that is central to the new field of conservation medicine. The product of a growing coalition of conservation biologists and ecologists, wildlife veterinarians, and biomedical researchers, conservation medicine explicitly addresses the interlinked and transdisciplinary nature of many of today's most urgent health and conservation issues. The field is being advanced most forcefully by researchers associated with the recently established Consortium for Conservation Medicine (CCM). Originally established in 1998 within the School of Veterinary Medicine at Tufts University, CCM consists of three partner organizations representing the veterinary, wildlife conservation, and human health components of conservation medicine. Collaborating with Tufts are Wildlife Trust, a US-based wildlife conservation organization, and the Center for Health and the Global Environment at Harvard Medical School. The advent of conservation medicine is timely. In this era of widespread environmental degradation, declining biodiversity, and emerging diseases in both humans and animals, many medical experts and conservationists agree with conservation medicine's defining theme: The concept of healthâfor both humans and animalsâmust be understood in an ecological context. One of the aims of conservation medicine is to formalize and advance this multidisciplinary perspective. âHealth connects all species on the planet,â said Philip Kosch, dean of the Tufts University School of Veterinary Medicine, in introducing a special symposium on conservation medicine at the June 2000 meeting of the Society for Conservation Biology in Missoula, Montana. Much of the focus at the symposium was on the complex problem of emerging diseasesâthat is, those with increasing incidence or geographic range. âThere are almost no examples of emerging wildlife diseases not driven by human environmental change,â said Peter Daszak, a disease ecologist at the University of Georgia. âAnd few human emerging diseases don't include some domestic animal or wildlife component.â Proponents of conservation medicine argue that, just as an ecological perspective can aid health workers in understanding the mechanisms of disease, adopting a medical model can benefit conservationists. Most directly, the integration of the veterinary community's biomedical perspective with the theoretical, ecological focus of conservation biologists can inform efforts to preserve biodiversity. At the same time, a focus on human health may be an effective way to âsellâ biodiversity protection programs to the public, both in the United States and around the world. Some conservation biologists hope that their basic environmental message will garner greater authority and respect when delivered by doctors and public health officials. Despite the enthusiasm of ecologists for the concept of conservation medicine, other observers take issue with a few of the field's claims and assumptions. Members of some veterinary and biomedical organizations point out that they already have a long history of dealing with issues at the interface of public health, wildlife health, and conservation. Beyond these mostly territorial disputes are other, more serious concerns. Some biologists, for example, question the assumption that conservation efforts can only benefit from a strong linkage with human health issues. Clearly, conservation medicine is a field that is still trying to define itself. But whether it is new in substance or in name only, the problems it has staked out are substantial ones. âHuman and animal populations are more mobile than ever before,â notes Mark Pokras, a Tufts University veterinarian who helped organize CCM. âAt the same time, wildlife habitat is decreasing and populations are declining and under stress. We're seeing an accelerating trend of exchange of disease among taxonomic groups, and it's going to get a lot worse over the next hundred years.â Richard Ostfeld, an ecologist at the Institute of Ecosystem Studies in Millbrook, New York, says conservation medicine has an important role to play in making explicit the linkages between wildlife veterinary medicine, conservation biology, and epidemiology. âThere really hasn't been any unified field that combines these perspectives,â he says. Conservation medicine provides a formal disciplinary framework within which scientists can piece together an understanding of the processesâspanning all levels of biological organization, from cells to ecosystemsâthat comprise the ecological context of health. Such an approach is a radical shift away from viewing diseases solely in terms of the response of individual organisms to infection or the spread of infection through populations. Consider Lyme disease, for example. Ostfeld has spent years unraveling the ecology of this tick-transmitted disease, which affects tens of thousands of people annually in North America and Europe. âTo a physician,â he says, âa case of Lyme disease begins when a patient enters a clinic complaining of symptoms. But to an ecologist, that visit to the clinic is the culmination of a series of events that began one to two years earlier and involved several different speciesâticks, mice, deer, oak trees, bacteriain nature.â In forests of the northeastern United States, the white-footed mouse is the most efficient host for transmitting Borrelia burgdorferi, the Lyme disease bacterium, to ticks. Lyme disease risk is governed by two factors: the percentage of tick nymphs infected with the disease organism and the absolute density of infected nymphs. The greater the summer abundance of white-footed mice, the greater the abundance of infectious tick nymphs the following year. When mouse populations are low, chances are greater that a larval tick will parasitize some other, nondisease-carrying species and thus will remain uninfected. The same is true when mice coexist with a diverse assembly of potential tick hosts. Through this âdilution effect,â Ostfeld has shown, increased biodiversity directly reduces the infection rate of ticks. When species diversity is reducedâand especially when predators of mice are eliminatedâboth mouse and tick densities climb steeply, and disease risk to humans increases. Ostfeld's data show that the small habitat patches in fragmented forests support few vertebrate species and large mouse populations with a high rate of B. burgdorferi infection. The work is still in progress, but if Ostfeld's data continue to support his hypothesis, the implication for land management is significant: Maintaining forests with high vertebrate diversity and healthy predator populations can directly benefit human health. Ostfeld and coworker Felicia Keesing are also investigating the possibility that a diverse assemblage of potential hosts might reduce the risk of other vector-borne diseases. Although more data are needed, Ostfeld says, âWe think this dilution effect is likely to be very widespread.â The case of Lyme disease is unusual only in the degree to which its ecology is understood. The emergence or reemergence of vector-borne diseases worldwide is nearly always the result of ecological changes affecting human, animal, and pathogen populations. Habitat loss and fragmentation, the disruption of food webs and other ecological relationships, environmental contamination, and climate change all contribute to new patterns in the manifestation and spread of disease. Thus, complete understanding of the human health risk posed by emerging diseases must include knowledge of causes that lie outside the traditional domain of physicians and epidemiologists. Most emerging infectious diseases in humans result from exposure to zoonotic pathogens, organisms that invade and complete some portion of their life cycle in other animals. Any changes in the density, distribution, population dynamics, or ecological interactions of host animal or insect vector species may result in new patterns of disease incidence. For example, work by Jonathan Patz of the Johns Hopkins School of Public Health has shown how deforestation in northern Peru has produced vast areas of prime habitat for Anopheles darlingi, the mosquito species that is the main vector for the malaria parasite in South America. Dense forest habitat, which favored other Anopheles species less likely to carry the disease, has given way to sunlit areas with a thin soil layer and standing pools of waterâconditions in which the malaria-carrying A. darlingi thrives. From 1987 to 1997, the incidence of malaria in the region increased sixfold. Climate change is another factor driving the expansion of malaria, encephalitis, and other diseases into new geographic regions. In the southwestern United States, recent changes in rainfall patterns have been linked to increases in rodent populations, which in turn lead to outbreaks of vector-borne diseases such as plague and hantavirus pulmonary syndrome. Morover human populations are changing and expanding, and the increased movement of people and materials around the world are creating new opportunities for the transfer of disease from wildlife to humans. Human encroachment into formerly isolated habitats has been associated with the emergence in people of previously unknown pathogens such as the Ebola virus and the human immunodeficiency virus. The recent appearance of West Nile virus in the eastern United States is a perfect example of a disease agent emerging in a novel location and ecological setting. First discovered in the Western Hemisphere in 1999, the virus was passed from infected birds to humans by mosquitoes. Over a dozen birds species, including a number of wide-ranging migrants, carry the virus. Ostfeld says the outbreak vividly illustrates the need for a transdisciplinary approach to disease research. A traditional medical and epidemiological investigation of West Nile virus, he notes, leaves many questions unresolved: âWhat role do American crows play in disease transmission? Why do mosquitoes in New York City's Central Park show very high infection prevalence, whereas mosquitoes in rural upstate New York show little or no infection? What impact does the pathogen have on wildlife populations? Answers to these questions require interdisciplinary or collaborative approaches, and conservation medicine can provide an important framework for such explorations.â Conservation medicine, proponents claim, does more than recognize the ecological context of health. It may also play an important role in protecting biodiversity. Although a small but active group of veterinarians have long focused on the health and conservation needs of wildlife populations, coordinated efforts drawing on the expertise of both field veterinarians and ecologists have been more the exception than the rule. Proponents believe that conservation medicine can both clarify the need for such a unified approach and provide the theoretical and logistical foundation for such efforts. At the same time, by emphasizing the human health costs of environmental damage, conservation medicine has the potential to leverage public understanding and support for protecting species and natural systems. In an October 1999 editorial in Conservation Biology, journal editor and University of Florida ecologist Gary Meffe wrote that âan added biomedical perspective surely would give conservation biology a higher public profile and offer even stronger arguments for biodiversity protectionâŚ. Strong scientific links between conservation biology and human health could be our most powerful tool in reaching larger expanses of humanity.â The need for a biomedical perspective in conservation efforts can be seen most clearly in the case of emerging diseases that threaten wildlife. Just as cholera, malaria, and tuberculosis pose a resurgent threat to human beings, a growing number of infectious diseases in both captive and wild animal populations now threaten wildlife species. In a recent review article (Science 287: 443â449) Peter Daszak and several coauthors surveyed a large number of terrestrial wildlife diseases that can be classified as âemergingâ on the basis of criteria such as increased geographic range, appearance in new populations, and increased incidence. Perhaps the best example is the fungal disease chytridio mycosis in amphibians. Outbreaks of the disease have caused mass die-offs of frogs and salamanders in different parts of the world, including Central America and Australia. âThis is probably the most significant emerging disease in wildlife,â Daszak commented. Chytridiomycosis is particularly alarming because it has appeared in relatively undisturbed habitats, can affect a wide variety of amphibian hosts, and has caused population declines and possibly extinctions in widely separated geographic regions. Just as European expansion in previous centuries introduced novel pathogens such as smallpox to aboriginal populations in the Americas and Australia, the growing international movement of people and livestock has resulted in the spread of diseases affecting wildlife. This globalization of infectious diseases is continuing at an accelerating rate, and the transfer of pathogens among humans, domestic animals, and wildlife occurs in all directions. Daszak describes a âhostâparasite ecological continuumâ within which various environmental changes and disruptions facilitate the spread of disease across taxonomic boundaries. Mountain and lowland gorillas, for example, are susceptible to many human diseases. Among them is the measles virus, which tourists may unwittingly introduce to gorilla populations, with devastating consequences. A greater threat to wildlife may be diseases spread by domestic animals. Canine distemper and rabies, spread by domestic dogs, have led to declines and local extinctions in African wild dogs. A domestic chicken pathogen is believed to be the cause of myco plasmal conjunctivitis in wild house finches, a fatal disease that has spread throughout the eastern United States since its introduction in 1994. The global exchange of agricultural materials, domestic animals, food products, timber, and biologically contaminated wastes has resulted in a phenomenon Daszak terms âpathogen pollution.â Pathogens introduced into immunologically naive host populations can have catastrophic effects on wildlife. In the late 1800s an outbreak of the morbillivirus disease rinderpest, originating in cattle imported from India, swept through Africa, decimating native ungulate populations. Introduced diseases contributed to the extinction of several native Hawaiian bird species. Like other forms of pollution, exotic pathogens now appear in remote and seemingly pristine habitats, as exemplified by the presence of a domestic chicken pathogen, the infectious bursal disease virus, in Antarctic penguins. As health pressures on both humans and wildlife mount, scientists from the biomedical and conservation communities are responding by joining forces. Although some issues clearly demand expertise from multiple disciplines, forging a coalition among ecologists, conservation workers, and health professionals is not easy. âWe need to develop a common respect, a common language, and a common set of priorities,â Pokras says. âWe have to bridge the gap between the people in muddy boots and jeans and those in white coats.â Forging a new coalition of health researchers is part of the goal of CCM. The consortium began as an outgrowth of established Tufts programs in international veterinary medicine and wildlife medicine. Pokras says that Tufts veterinarians were seeking ways to expand their involvement in conservation issues when they were approached by Wildlife Preservation Trust International (now Wildlife Trust), a group with over two decades of experience out field and conservation programs around the world. said to are wildlife conservation work in a number of and are wildlife health issues that as conservation biologists are not to Pokras says. 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In June the Office of Management and Budget proposed new, congressionally mandated guidelines to ensure the quality of the data gathered and disseminated by federal agencies. The new law augments the Paperwork Reduction Act, which already requires federal agencies to adopt processes to ensure data quality. Many scientists, however, worry that the guidelinesâwhich require agencies to devise and implement procedures that make it possible for individuals to challenge the accuracy of agency informationâcould impede or prevent the flow of scientific information and undermine the peer review process. Comments submitted to OMB by 55 scientific societies and academic institutions, including the American Institute of Biological Sciences, supported the intent of the law. âAs biomedical researchers whose work depends on the excellence of our own data, we are acutely aware of and sensitive to the importance of accurate data,â wrote Robert Rich, M.D., president of the Federation of American Societies for Experimental Biology (FASEB). The problem, scientists say, is not with the intent of the law but with the vagueness of the guidelines OMB proposes for implementing it. In particular, scientists argue that challengers seeking a correction of an agency's data should have expertise in the subject matter and should disclose any financial interest at stake in the outcome of the challenge. There should be a clear burden of proof on the person or group who made the initial charge to demonstrate why the data being challenged are inaccurate or wrong, added Elaine Hoagland, national executive officer for the Council on Undergraduate Research. Further, the OMB rules should contain adequate safeguards against frivolous challenges of scientific information. Those safeguards should allow government agencies to insist on the same degree of rigor and objectivity required of the original science, says Stephen Heinig, senior staff associate at the Association of American Medical Colleges (AAMC). âScientists can fight out issues of data and methodology in the literature,â Heinig says. âThat's the standard. We don't see any reason to change it.â And, noted AAMC President Jordan Cohen, the procedures mandated by the guidelines will be burdensome to agencies, whose staffâalready struggling to meet core missionsâwill have to shoulder supervisory and reporting tasks that contribute little to the agencies' missions. Citing âerrorsâ in Environmental Protection Agency data, as well as the sheer volume of information that EPA and other government agencies post on the Internet, Jim Tozzi explains that âwe felt the need to ensure the quality of government data.â Tozzi, a former OMB official who is now a board advisor to the Center for Regulatory Effectiveness, an independent policy group that helped draft the new law, calls the debate over OMB's data quality proposals âa big hullabaloo over nothing.â Not so, say Washington's scientific and educational groups. âThere is plenty of potential here for mischief,â notes Richard Harpel, director of federal relations for the National Association of State Universities and Land Grant Colleges. In part, that is because the draft guidelines are very subjective, says Joanne Carney, director of the Center for Science, Technology and Congress at the American Academy for the Advancement of Science. Robert Wells, president of the American Society for Biochemistry and Molecular Biology, expressed the views of many scientific societies when he pointed out that key terms in the guidelines are not defined: âOMB asked for comment on the definitions of the terms âquality,â âutility,â âobjectivity,â and âintegrityââŚÂˇ [but] we are unable to find any definitions of these terms in the proposed guidelinesâŚÂˇ. It may seem to the drafters of this proposal that these terms are self-explanatory, but in fact they are not, at least as far as science and regulatory policy are concerned.â It isn't even clear who will be covered by the guidelines, which are silent on the question of applicability to federal grant recipients. âAny attempted federal restriction on dissemination of academic research would be wholly unacceptable in principle and would likely raise First Amendment considerations,â Heinig wrote. The guidelines âshould specifically exclude academic and other non-federal institutions performing research under federal grants.â FASEB's Rich questioned OMB's proposal that government data âbe substantially reproducible upon independent analysis.â âWho will conduct these [independent] studies and who will pay for them?â he wondered. âHow can research studies [that] may have taken place over a period of years and used biological substances be âsubstantially reproducedâ?â Rich also faulted OMB's proposal that federal agencies report the number and nature of complaints regarding their compliance with the guidelines. âThe number of complaints received rather than the validity of the complaints could unfairly impact the reputation of an agency and//or its funded investigators,â he wrote. âA large number of complaints on a scientific matter could simply reflect a controversial issueâŚÂˇrather than the excellence of the science.â The bottom line, Harpel says, is that by seeking to ensure high-quality scientific data, OMB could interrupt ongoing research and leave government agencies and their researchers open to harassment by special interests. That, he states, would âmake it harder to be a scientist.â