On the origins and development of evidence-based medicine and medical decision making

The aims of this paper are to identify the issues and forces that were the impetus for two recent developments in academic medicine, evidence-based medicine (EBM) and medical decision making (MDM); to make explicit their underlying similarities and differences; and to relate them to the fates of these innovations. Both developments respond to concerns about practice variation; the rapid growth of medical technology, leading to a proliferation of diagnostic and treatment options; the patient empowerment movement; and psychological research that raised questions about the quality of human judgment and decision making. Their commonalities include: use of Bayesian principles in diagnostic reasoning, and the common structure embedded in an answerable clinical question and a decision tree. Major differences include: emphasis on knowledge or judgment as the fundamental problem; the status of formal models and utility assessment; and the spirit and tone of the innovation. These differences have led to broader acceptance of EBM within academic medicine, while decision analysis, the fundamental tool of MDM, has been less welcomed in clinical circles and has found its place in guideline development, cost-effectiveness analysis, and health policy.     

Human ovarian granulosa cells and follicular fluid indices: the relationship to oocyte maturity and fertilization in vitro

The study investigates the correlation between oocyte maturity and fertilization and a variety of hormonal parameters in follicular fluid and ovarian granulosa cells. A methodology for purification of granulosa cells from contaminating blood cells is also established. A total of 63 follicular aspirates were collected at oocyte retrieval from 30 women superovulated using the long luteinizing hormone- releasing hormone (LHRH analogue)/human menopausal gonadotrophin regimen. Oestradiol, progesterone, testosterone and human chorionic gonadotrophin (HCG) were quantified in follicular fluid and granulosa cells were immunostained for human chorionic gonadotrophin. Immunopurification of granulosa cells from contaminating blood cells was performed. HCG in follicular fluid was significantly high in follicles yielding immature (grade 3) oocytes (P=0.002); there was no correlation with fertilization. Aspirates from follicles containing mature (grade 1) oocytes and oocytes that subsequently fertilized had significantly more granulosa cells immunobound to HCG (P < 0.001, P=0.02). Moreover, the immunomagnetic purification technique provided >98% pure population of granulosa cells. The data demonstrate that HCG in follicular fluid and on granulosa cells may help to predict oocyte maturity and fertilization. Furthermore, immunomagnetic beads provide a reliable procedure for the purification of ovarian granulosa cells.      

Continuing medical education for life: eight principles.

Continuing medical education (CME) is being pressured to change in response to increasing and changing educational needs of practicing physicians, fostered by technical innovations, evolution of practice styles, and the reorganization of health care delivery. Leadership in the reform of CME falls primarily to the medical specialty societies in light of their traditional responsibilities for accrediting CME and maintaining professional standards. To address the need for reform, the American College of Obstetricians and Gynecologists in 1997 organized a conference to assemble CME program administrators from several medical specialties and academicians with expertise in postgraduate learning. At the conference, issues facing CME were examined. The authors, who were conference participants, state and explain eight principles that emerged from conference discussions. (For example: "Educational activities should be supportive of and coordinated with the transition to evidence-based medicine.") The principles reflect the interspecialty and interdisciplinary consensus achieved by the conference participants and can serve as useful guideposts for educators as they work to improve CME in their institutions. The authors conclude by noting the need for a more systematic and rigorously analytic approach, where CME content is determined according to assessed needs and CME is evaluated by measuring outcomes; for this to happen, CME educators and faculty must be brought up to date through training, including the use of problem-based learning. CME must also instill collegiality, interaction, and collaboration into the learning environment instead of being a solitary learning activity. Finally, CME must not only emphasize the acquisition of knowledge but also instruct physicians in the process of decision making to help them better use their knowledge as they make clinical judgments.     

Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.     

C7 complement deficiency in an Israeli Arab village

Deficiencies of terminal complement components, particularly the latter ones, are often detected because of increased susceptibility to Neisserial infections. Herein we document the first report of C7 deficiency among a highly inbred Arab population living in the lower Galilee region of Israel. Both biochemical and molecular analysis were performed on samples from infected survivors and parents of children who succumbed to Neisserial infections in a 4-year period. Only the index case who suffered recurrent infections and a sibling who had not suffered an infection during the outbreak were found to be C7-deficient. The mutation was found to be the one previously described to be prevalent among Israeli Jews of Moroccan ancestry (mutation G1135C). The implications of this finding are discussed in the context of family pedigree, the protective effect of complement deficiency, and the clinical outcome.     

Ethical considerations for enzyme replacement therapy in neuronopathic Gaucher disease

Elstein D, Abrahamov A, Zimran A. Ethical considerations for enzyme replacement therapy in neuronopathic Gaucher disease. Clin Genet 1998: 54: 179–184. 0 Munksgaard, 1998
Enzyme replacement therapy for Gaucher diseases, the most prevalent lysosmal storage disease, was originally approved by the FDA for type I patients and has proven to be both safe and effective in reducing hepatosplenomegaly and improving the hematological parameters. However, the use of enzyme treatment in both neuronopathic forms has heretofore been on an investigational or trial basis, with reports of progression of neurological deterioration even at very high doses. To date, there are no guidelines for clinicians with regard to enzyme replacement therapy in the neuronopathic forms of metabolic diseases. Herein, we discuss strategies derived from the literature ub-his treatment of very premature babies and from the Jewish Halachic point of view. In conclusion, we describe recommendations for the ethical treatment and/or withdrawal of treatment. as well as practical guidelines for dosage regimens, in children with neuronopathic Gaucher disease.     

Progestagen-releasing vaginal rings--an update

Marketing of an intravaginal ring that releases a progestagen at low dosage willbegin in 1985. The device is a silicone rubber toroidal ring 55.6 mm in diameter. Its active constituent is 5 mg of levonorgestrel, with an in vivo release rate of 20 mcg/day. The device is left in the vagina for 3 months, at which point a new ring is fitted. The device largely acts locally on the genital tract, altering cervical mucus so that it is relatively inpenetrable to sperm. Over 50% of cycles in device acceptors are ovulatory; 19% have inadequate luteal function and 29% are anovulatory. In a social acceptability study involving 27 ring users, all participants asserted at the 8 week follow up that the ring was the best method they had used and indicated an interest in continuing to use the device. Over 50% cited health reasons for this choice. The ring was viewed as less invasive than the IUD and more convenient than the diaphragm. The greatest criticism of the ring resulted from changed menstrual patterns; in most cases, however, it was the unexpectedness of the change rather than the change itself that concerned the user. Clinical trials have suggisted that the ring is viable in terms of its safety, efficacy, and overall acceptability. The pregnancy rate in 5500 woman-months of experinence stands at 3%, and there has been no evidence of an increased incidence of actopic pregnancy. Although 20% of women experienced expulsion of the device, only 2% discontinued use for thes reason. The continuation rate of 60% after 1 year's use compares favorably with other methods of hormonal contraception.     

An efficient multiple-exposure analysis of the toxicity of crisnatol,a DNA intercalator in phase II clinical trials

To investigate the toxicity and mechanism of action of crisnatol (CRS), a new DNA intercalator currently in phase II clinical trials, we analyzed cellular and nuclear flow cytometric (FCM) parameters of murine erythroleukemic cells (MELC) exposed to a range of CRS concentrations over three exposure conditions: short-term (4 h), long-term (24 h), and short-term with recovery (4 h⁺/19 h^–). At 0.5–1.0M CRS, 4 h exposure results in a reversible G₂-phase block, while 24 h exposure results in > G₂ polyploidy. At 5–10M CRS concentrations, cells exhibit persistent retardation of S-phase progression or irreversible G₂ and/or > G₂ blocks, depending on duration of exposure. Cells terminally blocked in G₂ exhibit increased nuclear/cellular volumes and increased nuclear fluorescein isothiocyanate (protein) staining, suggestive of unbalanced growth. At 25–50M CRS concentrations, MELC exhibit severe membrane perturbation (loss of viability) regardless of exposure. In contrast, following similar exposures to an inactive isomer of CRS, MELC exhibit minimal cell cycle effects, suggesting that cell cycle kinetics may be a useful criterion for assessing potential efficacy. Similar analyses with different classes of chemotherapeutic agents reveal that the range of induced cellular/nuclear perturbations varies with the class of compound used. Taken together, these results suggest that drug toxicity can vary with both concentration and duration of exposure and, as such, a selective multiple-exposure FCM analysis may better represent the spectrum of drug action for drug development and pharmacodynamic studies.Abbreviations m-AMSA amsacrine - ARA-C cytosine arabinoside - BrdU 5-bromodeoxyuridine - CF 5,6-carboxyfluorescein - CFDA 5,6-carboxyfluorescein diacetate - CRS crisnatol - FCM flow cytometry - FITC fluorescein isothiocyanate - 5-FU 5-fluorouracil - DMSO dimethylsulfoxide - MELC Friend murine erythroleukemic cell - MLP melphalan - PBS phosphate-buffered saline - PI propidium iodide - TAX taxol - topo topoisomerase - VBL vinblastine sulfate - cis-Pt cis-platinum