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The three-decision problem in medical decision making.

Medical researchers and policy makers face decisions that require a choice from among two or more alternatives. Whereas traditional hypothesis tests cannot always serve the needs of the practitioner who needs to make a decision, a problem formulation that assigns losses to various incorrect decisions offers several advantages. With three possible decisions this approach offers a precise representation of the pragmatic and explanatory views of decision making. It enables the investigator to incorporate in the problem specification his attitudes about the seriousness of various errors by guiding him, before he sees the data, to a choice of asymmetric tail probabilities. It also suggests a reformulation of the P-value that can accommodate some of the difficulties practitioners face.

Biometry↗

Risk management frameworks for human health and environmental risks.

A comprehensive analytical review of the risk assessment, risk management, and risk communication approaches currently being undertaken by key national, provincial/state, territorial, and international agencies was conducted. The information acquired for review was used to identify the differences, commonalities, strengths, and weaknesses among the various approaches, and to identify elements that should be included in an effective, current, and comprehensive approach applicable to environmental, human health and occupational health risks. More than 80 agencies, organizations, and advisory councils, encompassing more than 100 risk documents, were examined during the period from February 2000 until November 2002. An overview was made of the most important general frameworks for risk assessment, risk management, and risk communication for human health and ecological risk, and for occupational health risk. In addition, frameworks for specific applications were reviewed and summarized, including those for (1)contaminated sites; (2) northern contaminants; (3) priority substances; (4) standards development; (5) food safety; (6) medical devices; (7) prescription drug use; (8) emergency response; (9) transportation; (10) risk communication. Twelve frameworks were selected for more extensive review on the basis of representation of the areas of human health, ecological, and occupational health risk; relevance to Canadian risk management needs; representation of comprehensive and well-defined approaches; generalizability with their risk areas; representation of "state of the art" in Canada, the United States, and/or internationally; and extent of usage of potential usage within Canada. These 12 frameworks were: 1. Framework for Environmental Health Risk Management (US Presidential/Congressional Commission on Risk Assessment and Risk Management, 1997). 2. Health Risk Determination: The Challenge of Health Protection (Health and Welfare Canada, 1990). 3. Health Canada Decision-Making Framework for Identifying, Assessing and Managing Health Risks (Health Canada, 2000). 4. Canadian Environmental Protection Act: Human Health Risk Assessment of Priority Substances(Health Canada, 1994). 5. CSA-Q8550 Risk Management: Guidelines for Decision-Makers (Canada Standards Association, 1997). 6. Risk Assessment in the Federal Government: Managing the Process (US National Research Council, 1983). 7. Understanding Risk: Informing Decisions in a Democratic Society (US National Research Council, 1996). 8. Environmental Health Risk Assessment (enHealth Council of Australia, 2002). 9. A Framework for Ecological Risk Assessment (CCME, 1996). 10. Ecological Risk Assessments of Priority Substances Under the Canadian Environmental Protection Act (Environment Canada, 1996).11. Guidelines for Ecological Risk Assessment (US EPA, 1998b). 12. Proposed Model for Occupational Health Risk Assessment and Management (Rampal & Sadhra, 1999). Based on the extensive review of these frameworks, seven key elements that should be included in a comprehensive framework for human health, ecological, and occupational risk assessment and management were identified: 1. Problem formulation stage. 2. Stakeholder involvement. 3. Communication. 4. Quantitative risk assessment components. 5. Iteration and evaluation. 6. Informed decision making. 7. Flexibility. On the basis of this overarching approach to risk management, the following "checklist" to ensure a good risk management decision is proposed: - Make sure you're solving the right problem. - Consider the problem and the risk within the full context of the situation, using a broad perspective. - Acknowledge, incorporate, and balance the multiple dimensions of risk. - Ensure the highest degree of reliability for all components of the risk management process. - Involve interested and effected parties from the outset of the process. - Commit to honest and open communication between all parties. - Employ continuous evaluation throughout the process (formative, process, and outcome evaluation), and be prepared to change the decision if new information becomes available. Comprehensive and sound principles are critical to providing structure and integrity to risk management frameworks. Guiding principles are intended to provide an ethical grounding for considering the many factors involved in risk management decision making. Ten principles are proposed to guide risk management decision making. The first four principles were adapted and modified from Hattis (1996) along with the addition of two more principles by Hrudey (2000). These have been supplemented by another four principles to make the 10 presented. The principles are based in fundamental ethical principles and values. These principles are intended to be aspirational rather than prescriptive--their application requires flexibility and practical judgement. Risk management is inherently a process in search of balance among competing interests and concerns. Each risk management decision will be "balancing act" of competing priorities, and trade-offs may sometimes have to be made between seemingly conflicting principles. The 10 decision-making principles, with the corresponding ethical principle in italics are: 1. Do more good than harm (beneficence, nonmalificence).- The ultimate goal of good risk management is to prevent or minimize risk, or to "do good" as much as possible. 2. Fair process of decision making (fairness, natural justice). - Risk management must be just, equitable, impartial, unbiased, dispassionate, and objective as far as possible given the circumstances of each situation. 3. Ensure an equitable distribution of risk (equity). - An equitable process of risk management would ensure fair outcomes and equal treatment of all concerned through an equal distribution of benefits and burdens (includes the concept of distributive justice, i.e., equal opportunities for all individuals). 4. Seek optimal use of limited risk management resources (utility). - Optimal risk management demands using limited resources where they will achieve the most risk reduction of overall benefit. 5. Promise no more risk management that can be delivered (honesty).- Unrealistic expectations of risk management can be avoided with honest and candid public accounting of what we know and don't know, and what we can and can't do using risk assessment and risk management. 6. Impose no more risk that you would tolerate yourself (the Golden Rule). - The Golden Rule is important in risk management because it forces decision makers to abandon complete detachment from their decisions so they may understand the perspectives of those affected. 7. Be cautious in the face of uncertainty ("better safe than sorry"). - Risk management must adopt a cautious approach when faced with a potentially serous risk, even if the evidence is uncertain. 8. Foster informed risk decision making for all stakeholders (autonomy). - Fostering autonomous decision making involves both providing people with the opportunity to participate, and full and honest disclosure of all the information required for informed decisions. 9. Risk management processes must be flexible and evolutionary to be open to new knowledge and understanding (evolution, evaluation, iterative process). - The incorporation of new evidence requires that risk management be a flexible, evolutionary, and iterative process, and that evaluation is employed at the beginning and througthout the process. 10. the complete elimination fo risk is not possible (life is not risk free).- Risk is pervasive in our society, and cannot be totally eliminated despite an oft-expressed public desire for "zero risk". However, the level of risk that may ve tolerable by any individual is dependent on values of beliefs, as well as scientific information. Each agency must continue to employ a process that meets the needs of their specific application of risk management. A single approach cannot satisfy the diverse areas to which risk decisions are being applied. However, with increasing experience in the application of the approaches, we are evolving to a common understanding of the essential elements and principles required for successful risk assessment, risk management, and risk communication. Risk management will continue to be a balancing act of competing priorities and needs. Flexibility and good judgement are ultimately the key to successfully making appropriate risk decisions.

Canada↗

P-R-A-C-T-I-C-A-L: a step-by-step model for conducting the consultation in general practice.

BACKGROUND: It has been shown that when patients are unable to express all their major concerns, they are less likely to follow the physician's prescribed treatment plan and they are less satisfied. On the other hand, the GP has a limited amount of time to elicit all the appropriate information and must ask certain questions about the biological aspects of the illness in order to carry out her professional responsibilities. By acting in a patient-centred way, first enabling the patient to express himself, the GP can make maximum use of patients' ability for problem formulation and solution. METHODS: We describe a model, for which the mnemonic, P-R-A-C-T-I-C-A-L, will help the practitioner to remember its nine steps. The model uses a chronological succession of strategies during the consultation that balances the voices of medicine and the lifeworld. In overview, the GP takes the patient, step by step, first through an exploration and clarification of his views of the illness, then expands the problem by further examination (e.g. the physical examination), a negotiation about the final model of the illness that includes both diagnosis and management, a discussion of the treatment plan, and finally a moment of reflection to prepare for the next visit.

Abbreviations as Topic↗

The heuristic system. Precision and creativity in addiction treatment.

The Heuristic System (HS) is a method of developing case formulations for use in addiction treatment. Pertinent guidelines, models, or rules of thumb (heuristics) are applied in a stepwise process in order to generate at least two competing or complementary hypotheses concerning the clinical dynamics of the case. These hypothesis are then integrated and/or their relative utility for use in treatment is appraised. Key elements of HS include (a) a model of addiction based on cycles of self-experience, (b) a structured method for arriving at clinical problem formulations, (c) a schematic of the recovery process, (d) a menu of fundamental principles of substance abuse treatment, and (e) a format for providing updatable guidance to the patient for use in treatment. A case developed from the HS approach is presented. This article concludes with a discussion of the implications of HS theory and methods for program design and research.

Comorbidity↗

Formulation of benzoporphyrin derivatives in Pluronics.

This study investigates the potential of Pluronics for the formulation of tetrapyrrole-based photosensitizers, with a particular focus on B-ring benzoporphyrin derivatives. The B-ring derivatives have a high tendency to aggregate in aqueous solutions, and this poses a significant formulation problem. Pluronics are ABA-type triblock copolymers composed of a central hydrophobic polypropylene oxide section with two hydrophilic polyethylene oxide sections of equal length at either end. Out of a range of different commercially available block copolymers studied, it was found that the longer the hydrophobic block, the better the stabilization of tetrapyrrolic drugs in monomeric form in aqueous suspensions. Of these the best performance was observed in the micelle-forming Pluronic P123. Micelle size determination by laser light scattering confirmed that particle size in stable Pluronic formulations was around 20 nm. Pluronics such as L122 formed emulsions spontaneously without the need for emulsion stabilizers; emulsions were highly stable at ambient temperatures over several days and also highly effective as potential drug delivery agents.

Drug Delivery Systems↗

Tomography of joint P-wave traveltime and polarization data: a simple approach for media with low to moderate velocity gradients.

An elastic wave tomography method utilizing joint traveltime and polarization data is proposed that is computationally simpler than the existing methods [Hu and Menke, Geophys. J. Int. 110, 63 (1992); Farra and Begat, Geophys. J. Int. 121, 371 (1995)]. In the linearization problem for the use of polarization data, we start with ray perturbation theory and assume that the medium is weakly inhomogeneous. Then the problem formulation for polarization data is approximately expressed as a linear integral of the gradient of the medium slowness perturbation along a reference ray. We call this a quasi-linear approximation which ignores the effect of the perturbation of the ray position on the first-order perturbation of the ray slowness vector. To efficiently obtain the solution for multi-data sets, a quadratic objective functional is constructed by including the data misfit terms and a model constraint term. Then a new conjugate gradient type of iterative reconstruction algorithm is developed to solve this minimization problem. This algorithm is also an extension of the conjugate gradient approach for standard least-squares problems. The feasibility and capability of the proposed tomography method is illustrated by conducting both noise-free and noisy synthetic experiments in a cross-hole geometry. The numerical results demonstrate that the additional use of polarization data not only improves the image quality, but also has a stabilizing effect on the iterative tomography solution. However, the limitation of the method is that it becomes inaccurate if the velocity variations in the medium change rapidly with position.

Journal Article↗

Strengthening capacity in developing countries for evidence-based public health: the data for decision-making project.

Public health officials and the communities they serve need to: identify priority health problems; formulate effective health policies; respond to public health emergencies; select, implement, and evaluate cost-effective interventions to prevent and control disease and injury; and allocate human and financial resources. Despite agreement that rational, data-based decisions will lead to improved health outcomes, many public health decisions appear to be made intuitively or politically. During 1991-1996, the US Centers for Disease Control and Prevention implemented the US Agency for International Development funded Data for Decision-Making (DDM) Project. DDM goals were to: (a) strengthen the capacity of decision makers to identify data needs for solving problems and to interpret and use data appropriately for public health decisions; (b) enhance the capacity of technical advisors to provide valid, essential, and timely data to decision makers clearly and effectively; and (c) strengthen health information systems (HISs) to facilitate the collection, analysis, reporting, presentation, and use of data at local, district, regional, and national levels. Assessments were conducted to identify important health problems, problem-driven implementation plans with data-based solutions as objectives were developed, interdisciplinary, in-service training programs for mid-level policy makers, program managers, and technical advisors in applied epidemiology, management and leadership, communications, economic evaluation, and HISs were designed and implemented, national staff were trained in the refinement of HISs to improve access to essential data from multiple sources, and the effectiveness of the strategy was evaluated. This strategy was tested in Bolivia, Cameroon, Mexico, and the Philippines, where decentralization of health services led to a need to strengthen the capacity of policy makers and health officers at sub-national levels to use information more effectively. Results showed that the DDM strategy improved evidence-based public health. Subsequently, DDM concepts and practices have been institutionalized in participating countries and at CDC.

Bolivia↗

Teaching ethics using small-group, problem-based learning.

Ethics is the emphasis of our first-year Introduction to Clinical Medicine-1 course. Introduction to Clinical Medicine-1 uses problem-based learning to involve groups of seven to nine students and two facilitators in realistic clinical cases. The cases emphasize ethics, but also include human behaviour, basic science, clinical medicine, and prevention learning issues. Three cases use written vignettes, while the other three cases feature standardized patients. Groups meet twice for each case. In session one, students read the case introduction, obtain data from the written case or standardized patient, identify the case's ethical problems, formulate learning issues, discuss ways to resolve the moral conflicts, and assign research responsibilities. In session two, students discuss their assigned learning issues and specify and justify clinical actions to address the case's ethical dilemmas. Following three cases, groups write an essay discussing what they learned and describing how they would approach and resolve the case's learning issues.

Education, Medical, Undergraduate↗

A new approach to preparing students for academic medicine.

Critical thinking and self-directed learning by students are goals strongly endorsed by medical educators. Teaching medical interviewing and physical diagnosis skills is one of the most important tasks in medical school. An elective for fourth-year students was designed to address both areas. Ten senior medical students spent one month with a teaching staff member and fellow in general medicine. Part of the course was designed for independent problem-solving posed by sophisticated medical problems encountered in a general medicine practice. Skills in problem formulation, reading and assessing the medical literature, and communicating with peers were learned or improved. In the remainder of this course five pairs of senior students precepted 28 randomly chosen second-year students and taught medical interviewing and physical diagnosis. Techniques of teaching and basic pathophysiology were reviewed, and role-playing, feedback, demonstration and role-modelling were used.

Attitude of Health Personnel↗

Paclitaxel (taxol).

Paclitaxel is a novel antineoplastic that effects cytotoxicity by promoting intracellular tubulin polymerization and stabilizes abnormal microtubule structures against depolymerization. Although its clinical development had been hampered by misconceptions about its pharmacology, its scarcity, difficulties extracting it from its natural source, formulation problems, and frequent severe hypersensitivity reactions, paclitaxel recently was approved for treatment-refractory ovarian cancer. Two major adverse effects are dosage- and schedule-related myelosuppression and mucositis. Neurotoxicity is directly related to both the individual and cumulative doses. Other relevant toxicities are hypersensitivity reactions, effects on cardiac rate and rhythm, arthralgias and myalgias, generalized hair loss, and mild nausea and emesis. Continuing clinical studies will evaluate paclitaxel as initial therapy for ovarian cancer and its utility in other malignancies. In addition, major efforts are under way to develop alternative sources to increase the availability of taxene analogs and reduce our dependence on yew species.

Clinical Trials as Topic↗

Analysis of feed blends containing microencapsulated 2-ethyl-1-hexanol: verification of homogeneity and stability.

2-Ethyl-1-hexanol (2-EH) was nominated for carcinogenicity testing by the National Toxicology Program because it is a high-volume chemical and a major metabolite of di(2-ethylhexyl)phthalate, a known hepatocarcinogen and a known contaminant in blood storage bags. In addition to uses as an intermediate in the manufacture of plasticizers. 2-EH is also used as a solvent, a lubricant and as a finishing compound for paper and textiles. The preferred route of administration for the carcinogenicity studies was oral via the diet. However, feed blends containing neat 2-EH were not sufficiently stable for feed studies. Dosed feed blends prepared with neat 2-EH retained only 86% of the theoretical concentration after blending, and 46% of theoretical after storage for 2 days in a rat cage environment. Feed blends containing microencapsulated 2-EH were sufficiently stable for toxicity studies: no losses of 2-EH were observed after blending, feed blends stored for 7 days in a rat cage retained 99% of the theoretical concentration and blends stored in sealed containers at room temperature for 21 days retained 97% of the theoretical concentration. These studies demonstrate the potential for microencapsulation technology to eliminate dose formulation problems associated with volatile chemicals.

Animal Feed↗

Comparison of the antitumor activity of DTIC and 1-p-(3,3-dimethyl-1-triazeno) benzoic acid potassium salt on murine transplantable tumors and their hematological toxicity.

This study describes a comparison of 1-p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazeno) (DTIC) with reference to antitumor activity on different murine tumors and hematological toxicity. DM-COOK appeared comparably or slightly more effective in L1210, P388, and M5 tumors in the mouse. However, when the treatment of mice bearing M5 with DM-COOK was combined with surgical removal of the primary tumor, the host's life-span was highly significantly prolonged. The two drugs showed similar activity in an M5 variant selected for resistance to cyclophosphamide. In L1210 Ha, a leukemia that is spontaneously resistant to DTIC, DM-COOK was not effective. Both DM-COOK and DTIC caused transient leukopenia with a maximum WBC fall of 57% and 71% compared with control values. DM-COOK's greater chemical stability might be an advantage, as the decomposition of DTIC is thought to lead to products responsible for some toxic effects in humans. Like other phenyldimethyltriazenes DM-COOK, is a good candidate for clinical trials because its water solubility eliminates formulation problems.

Animals↗

Cultural phenomena and the research enterprise: toward a culturally anchored methodology.

Highlights the points at which culture intersects major phases of the research enterprise--problem formulation, population definition, concept and measurement development, research design, methodology, and data analysis--and influences and constrains what researchers deem worthy of investigation and how they interpret what they observe. These ethnocentric biases inhibit the development of a knowledge base for understanding diverse cultural communities. At each step of the research process, the need to carefully examine and expose the underlying cultural assumptions and to generate and develop alternative choices is emphasized. Guidelines are provided to encourage researchers to be aware of and deliberately make choices toward the development of a culturally anchored methodology that balances the demands for rigor and sensitivity.

Culture↗

Integrating environmental restoration and ecological restoration: long-term stewardship at the department of energy.

With the ending of the Cold War, several federal agencies are reclaiming land through remediation and restoration and are considering potential future land uses that are compatible with current uses and local needs. Some sites are sufficiently contaminated that it is likely that the responsible federal agency will retain control over the land for the foreseeable future, providing them with a stewardship mission. This is particularly true of some of the larger Department of Energy (DOE) facilities contaminated during the production of nuclear weapons. The use of the term "restoration" is explored in this paper because the word means different things to the public, ecologists, and environmental managers responsible for contaminated sites, such as Superfund sites and the DOE facilities. While environmental restoration usually refers to remediation and removal of hazardous wastes, ecological restoration refers to the broader process of repairing damaged ecosystems and enhancing their productivity and/or biodiversity. The goals of the two types of restoration can be melded by considering environmental restoration as a special case of ecological restoration, one that involves risk reduction from hazardous wastes, and by broadening environmental restoration to include a more extensive problem-formulation phase (both temporal and spatial), which includes the goal of reestablishing a functioning ecosystem after remediation. Further, evaluating options for the desired post remediation result will inform managers and policy-makers concerning the feasibility and efficacy of environmental restoration itself.

Journal Article↗

A Knowledge-Based Systems Approach to Design of Spatial Decision Support Systems for Environmental Management

/ This paper describes a framework for designing spatial decision support systems for environmental management using a knowledge-based systems approach. An architecture for knowledge-based spatial decision supportsystems (KBSDSS) is presented that integrates knowledge-based systems with geographical information systems (GIS) and other problem-solving techniques. A method based on spatial influence diagrams is developed for representation of environmental problems. The spatial influence diagram provides an interface through which knowledge-based systems techniques can be applied to build capabilities for problem formulation, automated design, and execution of a solution process. In addition to the flexibility and developmental advantages of knowledge-based systems, the KBSDSS incorporates expert knowledge to provide assistance for structuring spatial influence diagrams and executing a solution process that automatically integrates the GIS, data base, knowledge base, and different types of models. The framework is illustrated with a system, known as the Islay Land Use Decision Support System (ILUDSS), designed to assist planners in strategic planning of land use for the development of the island of Islay, off the west coast of Scotland.KEY WORDS: Geographical information systems; Spatial decision support systems; Knowledge-based systems; Spatial influence diagrams; Environmental management

Journal Article↗

Methuselah--an expert system for diagnosis in geriatric psychiatry.

This report is based on the notion that criteria for "successful" diagnosis differ for different medical specialties. Diagnostic judgement in highly unstructured task domains is best characterized as clinical problem formulation with pragmatic implications for interventions. This concept is illustrated by the implementation of a computer-based diagnostic expert system for geriatric psychiatry. The program begins with guiding the patient's interview by the clinician. This is followed by the diagnostic process which is conducted in three steps. In the first step, candidate syndromes of disease states are identified by matching the presenting complaints with symptom lists of clinical syndromes. In the second step, the candidate syndromes serve as the organizers for gathering additional patient data (e.g., information from referral source and past illnesses) to seek constellations of findings which form a coherent clinical context. In this phase, the program can also prompt the clinician to obtain additional information from the patient or other available sources to resolve conflicts or, if necessary, invoke the concurrent presence of two independent syndromes to attain convergence (i.e., minimize the number of unexplained findings). In a final step, the syndromes with highest credence value, reflected by the number of linkages to patient data, are sharpened to specific diagnostic formulations. This is accomplished by frames of diagnoses which are associated with each syndrome. Once again, the patient data can be consulted to achieve optimal matches. A summary statement to the clinician lists the essential supporting evidence for the chosen diagnosis and can communicate alternatives or unresolved issues for clarifying interventions. Although no decisive evidence is available, informal observations of clinicians support the notion that clinical reasoning in highly unstructured domains is largely contextual and seeks apprehension of "gestalts" in successive steps. The diagnostic program of this report aims at simulating this process.

Aged↗

A general approach for modelling and mathematical investigation of the human upper limb.

This paper is an attempt to systematize and solve the problems connected with biomechanical modelling and mathematical investigation of the upper limb, when all muscles acting on the shoulder, elbow and wrist joint are included. The basic problem is the assumption of a hypothesis for the unit vectors, collinear with muscle forces. The so-called segment-lines modelling of the muscle force direction is proposed for solving this problem. This approach combines the simplicity of the straight line joining the muscle tendon origin to the insertion point, its application for the analytical description of the model and the real description of the muscle anatomical functions. The principle of the anatomically adequate moment is the general criterion for choosing the segments (straight and curvilinear sections) by which the direction of the muscle action is replaced. The different optimization techniques which are used for solving the statically indeterminate problem, formulated for musculoskeletal biomechanical models, are considered. Aiming to obtain strictly positive and continuous solutions for the muscle forces moduli, the application of the Lagrange multipliers method is proposed. The possibility of applying different optimization criteria is explored. A general conclusion may be formulated: if there exists any criterion which is independent of the joint angles, it follows than that it must be dependent on the joint reactions and, in addition, it must be nonlinearly dependent on the muscle forces moduli.

Algorithms↗

Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update.

Based on the findings above, a number of conclusions can be made regarding the distribution, pharmacokinetics, and therapeutic range investigations with RAPA: (a) the majority of the drug is sequestered in erythrocytes, resulting in whole blood concentrations being considerably higher than plasma concentrations; (b) the drug is metabolized by the same cytochrome P450 3A enzyme involved in the metabolism of CsA and FK506. Metabolites are primarily simple demethylations and hydroxylations with 41-O-demethyl RAPA being the major metabolite both in vivo and in vitro; (c) the drug has a relatively long half-life in both humans and animals with 24-h trough concentrations being within the analytical range of HPLC when immunosuppressive doses are administered; (d) the drug exhibits a degree of proportionality between trough concentrations and dose; (e) a strong correlation exists between area under the concentration-time curve and trough blood concentration at steady state; (f) trough concentrations of the drug appear to be related to immunosuppressive efficacy and drug-related side effects; (g) the nephro- and neurotoxic properties of CsA are not augmented by concurrent treatment with RAPA; and (h) phase IIB trial results have shown a decrease of acute rejection episodes from 40% to < 10% among patients treated with full-dose CsA plus RAPA. The studies described here should provide a basis for the establishment of therapeutic monitoring protocols for RAPA. In addition, new derivatives of RAPA, such as SDZ RAD, designed to overcome formulation problems associated with RAPA, while maintaining similar pharmacokinetics and in vivo activity, show promise as alternatives to RAPA.

Animals↗