Proper preference-based outcome measures in economic evaluations of pharmaceutical interventions.
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Economics, Pharmaceutical↗
Biomedical subjects
A Gafni
Publications and source records attributed to A Gafni.
Direct kinetic evidence for triplet state energy transfer from Escherichia coli alkaline phosphatase tryptophan 109 to bound terbium.
The addition of excess Tb3+ to metal-depleted Escherichia coli alkaline phosphatase results in enhanced luminescence from enzyme-bound terbium, which increases with sample deoxygenation and exhibits a tryptophan-like excitation spectrum. Following pulsed excitation at 280 nm, the time-resolved terbium emission shows a negative prefactor associated with a submillisecond rise time, which is independent of the concentration of dissolved oxygen. The absence of a build-up phase and similarity in lifetime in the decay kinetics of directly excited (488 nm) terbium allows for the assignment of the submillisecond component in the 280 nm excited sample to bound terbium. The results of the steady state and time-resolved experiments suggest that the time evolution of alkaline phosphatase-bound terbium emission is determined by energy transfer (kET approximately 360 and 120 s-1) from the triplet state of tryptophan to terbium followed by terbium decay. This model is based on the observations that 1) the tryptophan phosphorescence lifetime (previously assigned to Trp109) corresponds to the longer component of the terbium emission and 2) the long-lived emission is enhanced, as is the Trp109 phosphorescence, by deoxygenation. An energy transfer mechanism involving the Trp109 triplet state is shown to be inconsistent with a dipole-dipole process and is best understood as a through-space electron exchange over a donor-acceptor distance of 9-10 A.
Alkaline Phosphatase↗
Photodegradation of tryptophan residues and attenuation of molecular chaperone activity in alpha-crystallin are correlated.
The major eye-lens protein alpha-crystallin is known to possess a remarkable sequence homology to the low molecular weight heat-shock proteins and has been shown to protect several proteins against thermally induced aggregation. In this work we demonstrate that the rapid aggregation of rabbit muscle phosphoglycerate kinase during incubation at 52 degrees C is completely inhibited in presence of 1/3 moles alpha-crystallin monomer per mole enzyme. Upon irradiation by UV light, tryptophan fluorescence intensity of alpha-crystallin declines, reflecting the destruction of these residues. A remarkable correlation is revealed between the reduction in alpha-crystallin fluorescence during UV-irradiation and the loss of its ability to protect phosphoglycerate kinase against aggregation. Since a loss of tryptophan fluorescence in intact eye lenses in vivo has been demonstrated to occur upon exposure to UV light, as well as during aging, it is proposed that the enhanced rate of lens opacification and cataract formation, as well as the increased levels of damaged lens proteins, which accumulate under these conditions, are the result of the gradual loss of the chaperone-protein efficacy of alpha-crystallin.
Aging↗
Physician supply in Ontario: further observations on SHARP and the SHARP projections.
In this issue (see pages 1395 to 1398) Eva Ryten questions the validity of the data that supported the projection of a surplus of physicians in Ontario over the next two decades, as presented in an earlier article in CMAJ by Denton, Gafni and Spencer. The authors maintain that the data they used were appropriate. Although the average annual growth rate for the early 1990s calculated from Ontario Health Insurance Plan (OHIP) billing data is somewhat lower than the rate they projected for the decade as a whole, the OHIP-based rate is much closer to their figure than Ryten's rate. They also disagree with Ryten in their belief that the recent reduction of medical school enrollment will have a negligible effect on the physician population by the year 2000. They argue too that Ryten misunderstands the nature of the imbalance they project between the availability of intern and resident services and the requirements for those services. Finally, the authors note that there is an argument for setting requirements for practising physicians at levels lower than they had assumed. For that reason, even if the supply of practising physicians were to grow less rapidly than projected, a substantial surplus could still result by the year 2000.
Humans↗
Phosphorescence reveals a continued slow annealing of the protein core following reactivation of Escherichia coli alkaline phosphatase.
When Escherichia coli alkaline phosphatase (AP) is refolded in vitro after extensive denaturation in 6.2 M guanidine hydrochloride, the enzymatic activity reaches its asymptotic value in 1 h at 24 degrees C. In contrast, the structural rigidity of the hydrophobic core of the protein, monitored by the recovery of the tryptophan phosphorescence lifetime, returns to its characteristic native-like value over several days. Moreover, the protein lability, measured by the rate of inactivation in 4.5 M guanidine hydrochloride, also changes on a time scale much longer than the recovery of activity. These results clearly demonstrate that while the return of enzymatic activity, the traditional measure of the attainment of the native state, indicates that AP has refolded to its final, active conformation, the phosphorescence data indicate otherwise. In the context of the rugged energy landscape model [Frauenfelder, H., et al. (1991) Science 254, 1598-1603], the slow annealing of the hydrophobic core is consistent with the presence of high-energy barriers that separate fully active intermediates along the folding pathway. The data suggest that the core of the protein undergoes continued structural rearrangements affecting the rigidity of the protein environment surrounding the emitting tryptophan and the protein lability long after the return of enzyme activity.
Alkaline Phosphatase↗
Nanosecond time-resolved circular polarization of fluorescence: study of NADH bound to horse liver alcohol dehydrogenase.
Circularly polarized luminescence (CPL) spectroscopy provides information on the excited-state chirality of a lumiphore analogous but complementary to information regarding the ground-state chirality derived from circular dichroism. The sensitivity of CPL spectra to molecular conformation makes this technique uniquely suited for the study of biomolecular structure, as extensively demonstrated in earlier studies. Unfortunately, the CPL spectra of many biomolecules often contain significantly overlapping contributions from emitting species either because multiple lumiphores are present (e.g., tryptophan residues in a protein) or because multiple conformations of the biomolecule simultaneously exist, each with a unique CPL spectrum. Increased resolution between individual contributions to the CPL may be achieved by time-resolving this signal, thus taking advantage of the fact that, as a rule, each of the emitting species also has a characteristic decay time associated with its electronically excited state. In addition, the time resolution provides information regarding dynamics associated with the different chiral states of the system. The present study describes an instrument for the determination of time-resolved CPL (TR-CPL) with subnanosecond resolution and its application to several chiral systems. The technique was first demonstrated on a model system with a strong time-dependent CPL signal. Subsequently, the circularly polarized component in the fluorescence of reduced nicotinamide adenine dinucleotide (NADH) bound to liver alcohol dehydrogenase was time-resolved. The CPL of NADH in the binary enzyme-coenzyme complex is time-dependent, reflecting structural differences around the reduced nicotinamide possibly due to a dynamic restructuring. In contrast, the CPL of the coenzyme in the ternary complex formed with enzyme and the substrate analog isobutyramide is essentially time-independent, likely reflecting a more rigid binding domain. Since the linear polarization of the fluorescence of the two complexes did not show any local flexibility of the NADH chromophore, the excited-state conformational rearrangement of the binary complex indicates a subtle change in its interactions with group(s) in direct contact with it.
Alcohol Dehydrogenase↗
Design and validation of a bedside decision instrument to elicit a patient's preference concerning allogenic bone marrow transplantation in chronic myeloid leukemia.
The objective of this study was to design and validate a bedside decision instrument to be used by patients with chronic myeloid leukemia and their physicians in deciding between the therapeutic alternatives of bone marrow transplantation and conservative management during the early phase of disease. A decision board was constructed containing detailed scenarios associated with the treatment alternatives, together with estimates of survival probabilities at various periods of followup. The instrument was tested on 42 healthy hospital personnel and validated by measuring the extent to which systematic alterations in the scenarios with respect to toxicities and survival probabilities produced predicted shifts in treatment preferences. A subgroup of respondents was randomized to receive information through the decision board alone or a shorter and less informative version of the instrument, followed by the decision board. The direction and strength of stated preferences were compared, together with satisfaction for these preferences. The direction and strength of preferences between bone marrow transplantation or conservative chemotherapy were influenced in a predictable way by changes in the toxicity and survival descriptions in the scenarios. Using the test-retest method in 16 subjects, the stated preferences were found to be highly reliable (intraclass correlation coefficient, 0.87). The mean level of satisfaction with the stated preference, on a scale from not at all satisfied = 1 to very satisfied = 5, was higher for those exposed to the decision board (3.7, SD 1.06) compared with those presented with the short version (2.95, SD 0.67) (P < 0.01). The results demonstrate the feasibility and acceptability of the instrument in healthy individuals. The preferences elicited by the instrument appear to be reliable and valid according to prespecified constructs of the relation between the information provided and the preferences predicted. These results support further testing of this approach in actual patients.
Bone Marrow Transplantation↗
More effective and less expensive: lessons from five studies examining community approaches to care.
Does the nature of community health services used by chronically ill clients and their caregivers have an impact on utilization of services, expenditure and well-being outcomes? A series of five studies, (four historic cohort and one randomized trial) examined clients suffering from a variety of chronic conditions in a number of community settings in different regions of Southern Ontario. Study sample composition and size varied. Each study was designed to quantify the well-being outcomes, and expenditure associated with different community approaches is covered under a nation-wide system of health insurance plans. As a collective, these studies represent increasing methodological rigor. Multiple-perspective client well-being outcome measures were used. Caregiver burden was also analyzed. A common approach to quantification and evaluation of expenditure for service consumption was applied across all five studies. The nature of community health services (proactive versus reactive approaches to care) was found to have direct and measurable impact on total expenditure for health service utilization and client well-being outcomes. A recurring pattern of lower expenditure for community health service utilization and equal or better client outcomes was associated with well-integrated proactive services when compared with individual fragmented, reactive approaches to care. The main lesson emerging from examining the five studies on approaches to community care is that it is as, or more, effective and less expensive to offer complete proactive health care services to chronically ill people in the early stages of their illness than to provide services on demand in a piecemeal manner.
Caregivers↗
Preferences for outcomes in economic evaluation: an economic approach to addressing economic problems.
In this paper we critically appraise the appropriateness and validity from an economic perspective of alternative preference-based approaches to measuring outcomes in economic evaluations of health care interventions. We describe the properties of an outcome measure for economic evaluation to make it compatible with the principles of economics when applied to the problem of resource allocation. We also describe the difference and similarities between the psychometric and the economic approaches for the measurement of outcome. Using these properties we critically appraise the use of QALY and HYE methods of measuring individual and social preferences for health outcome. We argue that the most advanced measure currently available that meets these required properties is the HYE. Because the HYE, unlike the QALY, has its foundations in utility theory under uncertainty, it neither assumes particular formulations of the individual utility function, nor is it incompatible with the principles of economics. As such it represents a further stage in the continuing development of methods for economic evaluation of health care programmes.
Evaluation Studies as Topic↗
The effectiveness and efficiency of health promotion in specialty clinic care.
Chronic illnesses make up the majority of health problems in North America. Many chronically ill persons adjust over time to their illnesses; however, there remains a small but important group of those less adjusted, who are concentrated in specialty clinics and are high users of health care resources. This randomized clinical trial investigated the impact of health promotion interventions in the form of problem-solving counseling or phone support that augmented conventional clinic medical care. Chronically ill, poorly adjusted outpatients (n = 293) attending clinics were randomly assigned to receive additional problem-solving counseling, phone call support, or neither. Psychosocial adjustment to illness, utilization, and expenditures of health services were the main outcomes measured. There were no overall significant differences between groups in their change in psychosocial adjustment and expenditures for health and social care. However, interaction analyses (P < 0.05) gave an indication of who might benefit from these interventions. Those who lived alone and infrequently used problem-solving behaviors to cope with their illness significantly improved their adjustment to illness and had fewer health service expenditures if they received problem-solving counseling. Supportive telephone calls were most effective for those who lived with someone and frequently used problem-solving coping behaviors. These findings suggest that health promotion services should be targeted to outpatients described by specific social support and coping characteristics.
Adaptation, Psychological↗
Very low-dose warfarin prophylaxis to prevent thromboembolism in women with metastatic breast cancer receiving chemotherapy: an economic evaluation.
PURPOSE: A recent double-blind, randomized trial demonstrated that very low-dose warfarin (VLDW) reduced the incidence of venous thromboembolism (VTE) without increasing the rate of bleeding in women with metastatic breast cancer receiving chemotherapy. We have evaluated the economic impact on the health care system of using VLDW in such patients. METHODS: The records of patients entered onto the trial and a simultaneous, fully allocated, costing model for a tertiary care hospital in Hamilton, Canada were used to determine the difference in costs associated with the care of patients with and without VLDW. RESULTS: The cost of providing VLDW was $ 21,854 (Canadian dollars) per 100 patients. This therapy led to a reduction in costs of $ 24,297 per 100 patients, thus saving the health care system $ 2,443 per 100 patients. In the sensitivity analysis, VLDW prophylaxis still did not increase health care costs unless the cost of VLDW was greatly increased, the cost of treating thromboembolic episodes was markedly reduced, or the incidence of either VTE or bleeding with VLDW was increased above the rates observed in the trial. CONCLUSION: We conclude that for women receiving chemotherapy for metastatic breast cancer, the benefits of VLDW can be realized without increased health care costs.
Breast Neoplasms↗
The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation.
PURPOSE: To develop a conceptual tool for the systematic development of cancer treatment practice guidelines. MATERIALS AND METHODS: The guidelines development tool, the Practice Guidelines Development Cycle, was derived from observing an evidence-based practice guidelines initiative at a comprehensive cancer center in Ontario, Canada, and from a literature review that uncovered barriers to guidelines development and implementation. Based on the literature findings and direct observations of how clinicians struggled with evidence-based guidelines development, we evolved a framework to incorporate clinical and administrative factors (eg, costs) into evidence-based guidelines. Use of the Practice Guidelines Development Cycle is illustrated with a clinical example (the use of adjuvant systemic therapy in good-risk, node-negative premenopausal breast cancer patients). RESULTS: The result is the Practice Guidelines Development Cycle, which consists of eight sequential steps, from topic selection to policy formulation. Independent validation of guidelines is included. The cycle products are the evidence-based recommendation, the practice guideline, and the practice policy. The main features of the cycle are emphasis on scientific evidence, acknowledgment of the roles of clinical experience and nonclinical (administrative) factors through consensus, and explicit separation of clinical and cost considerations in guidelines development. Twenty guidelines are currently in development. CONCLUSION: Attention to the barriers of guidelines development and the sociocultural nature of clinical practice, and respect for clinical experience, can lead to improved strategies for guidelines development.
Cancer Care Facilities↗
Breast irradiation postlumpectomy: development and evaluation of a decision instrument.
PURPOSE: To develop an instrument to help clinicians inform patients about the benefits and risks of breast irradiation following lumpectomy and to help an informed patient decide whether she prefers this treatment. METHODS: A Decision Board consisting of written material and visual aids was developed. It provides the patient with detailed information about her choices (breast irradiation or not), outcomes (breast recurrence and survival), probability of those outcomes, and quality of life associated with treatment and outcome. We studied the decision-making process in 82 consecutive node-negative lumpectomy patients who were seen in consultation by a radiation oncologist and oncology nurse. The Decision Board was used in the last 30 patients in the cohort. RESULTS: Patient comprehension following the consultation without the Decision Board was greater than 65% for all questions addressed, except for poor understanding of the lack of survival benefit associated with breast irradiation (12% of patients answered correctly) and that it could not be repeated (15% of patients answered correctly). Comprehension following the consultation with the Decision Board was similar, but understanding regarding the repetition of radiation (83%) was improved. Only 70% of patients in the no-Decision Board group felt they were offered a choice. This was increased to 97% in the Decision-Board group. Overall, 95% of patients chose breast irradiation, and this did not differ between groups. Patients reported several reasons for choosing breast irradiation, all of equal importance. CONCLUSION: The Decision Board facilitated shared decision making in node-negative lumpectomy patients who chose breast irradiation, but it did not affect a patient's choice to select breast irradiation.
Analysis of Variance↗
Problem-solving counselling or phone-call support for outpatients with chronic illness: effective for whom?
The purpose of this randomized controlled trial (RCT) was to determine the effectiveness of problem-solving counselling or phone-call support provided by nurses to outpatients not well adjusted to chronic illness. Subjects (N = 293) completed measures at baseline and after the six-month period of intervention for psychosocial variables including coping behaviours, purpose in life, and psychosocial adjustment to illness. Subjects receiving phone-call support from nurses demonstrated less psychological distress. Results also suggest that problem-solving counselling improves psychosocial adjustment to chronic illness for outpatients who live alone, infrequently use problem-solving coping skills, or frequently use avoidance coping methods. As well, outpatients with a low purpose in life who show infrequent use of problem-solving coping skills appear to benefit most from problem-solving counselling provided by nurses. On the other hand, those not well adjusted who frequently use problem-solving coping seem to be served more effectively by phone-call support.
Adaptation, Psychological↗
Evaluation of a home-based traction program for children with congenital dislocated hips and Legg Perthes disease.
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Child↗
Lack of correspondence between the room-temperature phosphorescence decay-components and Trp residues in a series of Trp-->Cys or Trp-->Phe mutants of human carbonic anhydrase II.
The room temperature phosphorescence of native human carbonic anhydrase (CA), and several mutants of this enzyme has been investigated. In these mutants the seven tryptophan residues in the native protein have sequentially been replaced by cysteine or phenylalanine. All of the mutants as well as native CA show room-temperature tryptophan phosphorescence (RTP) spectra. Surprisingly, only small differences in RTP life-times are noticeable among these mutants, indicating that there is more than one tryptophan residue with similar phosphorescence decay kinetics in the protein. The present results illustrate the danger in attributing the room temperature phosphorescence of a multi-tryptophan protein to a particular residue based solely on an analysis of the protein structure.
Carbonic Anhydrases↗
System for Health Area Resource Planning (SHARP): an application to Ontario medical school enrollment.
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Databases, Factual↗
Fluorescence detection of conformational changes in GroEL induced by thermal switching and nucleotide binding.
GroEL assists other proteins to fold in vivo, usually requiring Mg2+ and ATP to function. Electron micrographs reveal that ATP binding induces a conformational change in this protein. Previously we have suggested that a thermally induced conformational change in GroEL results in the switching between enhanced and arrested reactivation of bacterial glucose-6-phosphate dehydrogenase. This thermal switching occurs over a narrow temperature range (25-30 degrees C). Recently it has aslo been reported that the binding affinity of the P22 tail spike polypeptide to GroEL changes abruptly over this same temperature range. To determine whether these conformational changes occur in GroEL in solution in absence of folding intermediates, the protein was stoichiometrically labeled with AEDANS (N-(acetylaminoacyl)-5-naphthalene-1-sulfonic acid), a fluorescent label whose emission is environment-sensitive. By measuring changes in the fluorescence Stokes shift we have detected two thermally induced conformational changes between 25 and 30 degrees C. The first change occurs between 25 and 26 degrees C, resulting in less than a 1-nm shift in the fluorescence. The second conformational change occurs between 27 and 30 degrees C, resulting in a 3-nm fluorescence shift. The conformational change induced by ATP binding also results in a 3-nm shift in fluorescence. Our data provide a correlation between functional change and structural change in GroEL.
Adenosine Triphosphate↗