Undergraduate and postgraduate medical education in Canada.

An overview of medical education at both the undergraduate and postgraduate levels in Canadian faculties of medicine is provided. Particular attention is focused on changes that have occurred in the 1990s and their effect on medical students and on educational programs. Also considered are the effects of reductions in the number of entry-level positions for residency training and the changes in educational requirements for licensure on senior medical students.

Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease.

SUMMARY: We assessed the safety and surrogate markers' effect of acemannan as an adjunctive to antiretroviral therapy among patients with advanced HIV disease receiving zidovudine (ZDV) or didanosine (ddI) in a randomized, double-blind, placebo-controlled trial of acemannan (400 mg orally four times daily). Eligible patients of either sex had CD4 counts of 50-300/microl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry. CD4 counts were made every 4 weeks for 48 weeks. P24 antigen was measured at entry and every 12 weeks thereafter. Sequential quantitative lymphocyte cultures for HIV and ZDV pharmacokinetics were performed in a subset of patients. Sixty-three patients were randomized. All were males (mean age 39 years). The mean baseline CD4 counts were 165 and 147/microl in the placebo and acemannan groups, respectively; 90 percent of the patients were receiving ZDV at entry. Six patients in the acemannan group and five in the placebo group developed AIDS-defining illnesses. There was no statistically significant difference between the groups at 48 weeks with regard to the absolute change or rate of decline at CD4 count. Among ZDV-treated patients, the median rates of CD4 change (ACD4) in the initial 16 weeks were - 121 and - 120 cells per year in the placebo and acemannan groups, respectively ( p = 0.45), ACD4 from week 16 to 48 was 0 and - 61 cells per year in the acemannan and placebo groups (p = .11), respectively. There was no statistical difference between groups with regard to adverse events, p24 antigen, quantitative virology, or pharmacokinetics. Twenty-four patients, 11 receiving placebo and 13 receiving acemannan, discontinued study therapy prematurely, none due to serious adverse reactions. Our results demonstrate that acemannan at an oral daily dose of 1600 mg does not prevent the decline in CD4 count characteristic of progressive HIV disease. Acemannan showed no significant effect on p24 antigen and quantitative virology. Acemannan was well tolerated and showed no significant pharmacokinetic interaction with ZDV.

A phase I/II study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients with advanced human immunodeficiency virus infection.

In a phase I/II trial assessing the toxicity, pharmacokinetics, and activity of the (-)enantiomer of 2'-deoxy-3'-thiacytidine (3TC, lamivudine), 97 patients with AIDS or advanced human immunodeficiency virus (HIV) disease were administered 3TC at 0.5-20.0 mg/kg/day. The cohort's median entry CD4 cell count was 128/mm3 (range, 7-357). A toxic dose was not reached, although some patients reported mild headache, insomnia, and abdominal symptoms, and there was a general downward trend in neutrophil counts at the highest doses. Although subjective and difficult to interpret, increases in energy and appetite were noted, particularly in patients receiving > or = 8.0 mg/kg/day. Immunologic and virologic parameters showed evidence of at least transient anti-HIV activity at those higher doses. Although further studies of 3TC as monotherapy are needed, its favorable toxicity profile, evidence of at least transient clinical activity, and results of in vitro resistance experiments support further clinical testing in combination therapy.

Linking budgets to desired academic outputs at Dalhousie University.

In 1993, faced with continuing university budget reductions and dissatisfaction with the budget-allocation process, the Faculty of Medicine at Dalhousie University undertook a financial planning process. The goal was to develop a new resource-allocation model to better link academic budget support to desired academic outputs over a three-year period. Department heads categorized academic outputs (e.g., teaching, research, administration, and subcategories of these), determined their relative values (expressed as percentages of the total department budget to be projected), and identified acceptable units of measuring the outputs (e.g., for teaching in the first and second years of medical school, the unit was the number of teaching hours). When dollar values were assigned to the units of measure, the new model was used to calculate budget allocations for all departments. However, many departments showed large negative shifts in their budgets; these shifts were too large to be achieved within three years because of departments' contractual obligations. Therefore, a practical limit in budget shift was determined. This adjustment permitted a three-year projection of academic budgets to be made for each department. The use of the resource-allocation model has achieved the Faculty's goal by creating a better rationalization of budgets to academic outputs, but carries the risk that departments might abandon essential but "undervalued" academic activities.

Development of HIV-1 resistance to (-)2'-deoxy-3'-thiacytidine in patients with AIDS or advanced AIDS-related complex.

OBJECTIVE: To determine the rate of development of in vitro HIV resistance to (-)2'-deoxy-3'-thiacytidine (3TC) and relate the effect of dose to emergence of resistance. METHODS: HIV-infected men and non-pregnant women, aged > or = 18 years, with a CD4 count < or = 300 x 10(6)/l cells were followed in a Phase I/II study, in which they were evaluated for tolerance to 3TC and effect of this agent with regard to viral susceptibility. Peripheral blood and plasma samples were collected at regular intervals for analysis. HIV was isolated using umbilical cord blood mononuclear cells as targets. These cells were also used in determinations of median inhibitory drug concentration. Specific amplification of the 184 mutation site, associated with HIV resistance to 3TC, was performed by polymerase chain reaction, using specific primer pairs, on DNA harvested from infected peripheral blood mononuclear cells (PBMC) of donors or, alternatively, on DNA that had been reverse transcribed from plasma-associated HIV RNA. RESULTS: Phenotypic resistance was detected in approximately one-third of individuals studied, who were followed between 8 and 56 weeks. Development of 3TC resistance occurred independently of dose, although time of first appearance of resistant HIV-1 variants appeared reduced at high 3TC doses. Amino-acid changes at codon 184 in HIV-1 reverse transcriptase were associated with, and preceded, the development of phenotypic 3TC resistance. Most commonly, a Met to Ile substitution appeared transiently before being superceded by a Val substitution at codon 184. CONCLUSIONS: In vitro resistance to 3TC developed in a high proportion of subjects who received prolonged monotherapy with this drug. The development of resistance to 3TC was associated with appearance of mutated viral forms and the disappearance of wild-type virus, with regard to codon 184, in both patient plasma and PBMC.

Proposed guidelines for housestaff interaction with pharmaceutical companies.

The relationship between the medical profession and the pharmaceutical companies is complex, since industry depends on physicians for research and development, and for sales of its products. As a result, physician interactions with industry could undermine the patient-centered medical ethic, and jeopardize the physician-patient relationship. There is evidence that physicians are influenced by their encounters with the pharmaceutical industry. Particularly troubling is the increasing interaction of pharmaceutical companies and housestaff through detailing and educational support. Several studies have documented the pervasiveness of such relationships in training programs. Although professional bodies have developed criteria to help physicians in their dealings with the pharmaceutical industry, no principles have yet been formulated to address the unique aspects of resident contact with pharmaceutical companies. Guidelines designed to answer this need are proposed in this article.

Oral corticosteroids in patients with mild Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome (AIDS).

OBJECTIVE: To assess the effect of oral corticosteroids in patients with mild Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome (AIDS). DESIGN: Prospective, double blind, placebo controlled, randomized trial. METHODS: Included were AIDS patients having their first episode of P. carinii pneumonia, who had no other known active pulmonary pathology, who had no contraindications for corticosteroids and who had received no other anti-P. carinii medications for more than 48 h. Subjects received either prednisone, 60 mg/day for 7 days, followed by a progressive tapering over 14 days, or identical placebo. The present analysis pertains to patients with mild P. carinii pneumonia as defined by a baseline resting oxygen saturation greater than 90% and a decrease in oxygen saturation during exercise while breathing room air of not less than 5 percentage points. Early deterioration, the end-point of the trial, was defined as a 10% decrease from baseline oxygen saturation on day 3 or thereafter. RESULTS: At study termination, there were 12 subjects in the placebo group and 11 in the corticosteroid group. Baseline characteristics were not statistically different between the treatment groups. Early deterioration developed in 7 and 1 patients in the placebo and corticosteroid groups respectively (P = 0.027). In addition, by day 3, a number of parameters were less favorable in the placebo group relative to the corticosteroid group including median oxygen saturation (85% vs 97%; P = 0.003), lactic dehydrogenase (1514 vs 763; P = 0.013), median respiratory rate (30 vs 22; P = 0.003), median heart rate (100 vs 81; P = 0.002), and median temperature (39 vs 37; P = 0.024). Even though patients suffering early deterioration in the placebo group were switched to corticosteroids, significant differences between the groups remained at day 30 with regard to exercise tolerance. More than half of patients assigned to the corticosteroid group exercised for a median of 6.5 min on day 30 (P = 0.017). CONCLUSION: Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with mild AIDS-related P. carinii pneumonia as defined on the basis of pulse oximetry.

History of specialty residency funding in Canada.

Specialty residency training in Canada has evolved from its origin in teaching hospitals through an era dominated by universities to the present when public accountability is emerging as a dominant influence. The predominant educational strategies, including experimental learning, role modelling, continuum of training, independent thinking, self-directed learning and research experiences, have been influenced by the diversity of roles expected of the resident, including that of an employee, a student, a teacher and, more recently, a part of the policy instrument of governments in controlling physician resources.

Clinical correlates of in vitro HIV-1 resistance ot zidovudine. Results of the Multicentre Canadian AZT Trial.

OBJECTIVE: To describe the rate of development of in vitro HIV resistance to zidovudine (ZDV) and its prognostic implications within the Multicentre Canadian AZT Trial (MCAT). METHODS: HIV-infected subjects in Centers for Disease Control (CDC) stages IIB, III and IVC-2 with CD4 cell counts > 270 x 10(6)/l were treated with ZDV as part of a dose-range study. Participating volunteers underwent prospective clinical and laboratory evaluations at regular intervals. Viral cultures and sensitivity testing were performed every 12 weeks in a predefined subset of 50 volunteers. An isolate was designated ZDV-resistant if it had a median inhibitory concentration (IC50) for ZDV at least 50-fold higher than that of virus isolated from the same subject before initiation of antiviral chemotherapy. The relationship between resistance and subsequent disease progression was studied using the Mantel and Byar method, for which, at each instance of disease progression, 2 x 2 tables classifying progression versus resistance status were constructed. The observed number of progressions was compared with that expected under the null hypothesis using Mantel-Haenszel methods adjusted for baseline CD4:CD8 ratio. RESULTS: The Kaplan-Meier estimate for the cumulative development of in vitro resistance was 64% [95% confidence interval (CI), 41-78] at 180 weeks. Baseline CD4:CD8 ratio was negatively associated (P = 0.10) with the subsequent development of resistance (proportional hazard, 0.44; 95% CI, 0.17-1.10). After adjusting for baseline CD4:CD8 ratio, the numbers of observed and expected progressions following the development of resistance were 15 and 7.6, respectively (P = 0.008). A similar relative risk of progression between resistant and non-resistant states was found in the two CD4:CD8 strata; observed and expected progressions were 4 and 2.3 and 11 and 5.2 in the high and low CD4:CD8 strata, respectively. CONCLUSIONS: In vitro resistance to ZDV developed in 64% of subjects after 180 weeks of ZDV therapy. Lower CD4:CD8 ratio at baseline was associated with faster development of resistance. In addition, the development of resistance was found to be a marker of subsequent disease progression. This association persisted after adjustment for baseline CD4:CD8 ratio. Whether in vitro resistance to ZDV is merely a surrogate marker or a determinant of disease progression remains to be established.

Characterization of zidovudine resistant variants of HIV-1 isolated from patients on prolonged therapy.

As part of a clinical trial to assess zidovudine related toxic effects, the authors followed 48 initially asymptomatic individuals who received prolonged therapy with this drug at several tertiary care institutions. Blood samples had been obtained for viral isolation every three months and had yielded infectious HIV-1 progeny in over 94 percent of cases. After one year of therapy, over 30 percent of individuals had developed variants of HIV-1 that displayed in vitro resistance to zidovudine. Six of these zidovudine resistant variants of HIV-1 were compared with drug sensitive isolates obtained from the same subjects prior to initiation of treatment. The drug resistant variants were generally as infectious per mg viral protein for both susceptible T cell lines and peripheral blood mononuclear cells as the corresponding parental isolates from which they were derived. The drug resistance phenotype remained stable, in that zidovudine-insensitive species could still be identified, following many replication cycles in the absence of drug pressure. However, the percentage of zidovudine resistant viruses appeared to diminish in culture over time under such conditions. This was demonstrated by the fact that lower percentages of cells became infected in the presence of the drug, if the viruses used for infection had been propagated in the absence of the drug. In addition, higher concentrations of such viruses were required to initiate infection in the presence of the drug, and these viruses possessed lower IC50's for zidovudine. This suggests that zidovudine resistant variants of HIV-1 may be unlikely to possess any growth advantage in the absence of the drug.

Aerosol pentamidine-induced bronchoconstriction. Predictive factors and preventive therapy.

OBJECTIVE: To describe the frequency of aerosol pentamidine-induced bronchoconstriction, its relationship to non-specific airway responsiveness, and its response to preventive therapy using salbutamol, ipratropium bromide, or sodium cromoglycate. METHODS: Consecutive HIV-infected individuals starting prophylactic AP were eligible if they had not been previously treated with this agent. Simple spirometry was performed before and 10 min after a single 60-mg dose given through an ultrasonic nebulizer. Methacholine challenge was performed in all subjects 24 h to four days after the initial AP dose. Subjects with a change in FEV1 (delta FEV1) greater than or equal to 10 percent decrease after the initial AP dose were restudied on three separate occasions (greater than 24 hours apart) after premedication with two puffs of salbutamol (200 micrograms), ipratropium bromide (40 micrograms), or sodium cromoglycate (2 mg), in random order. RESULTS: Fifty-three subjects were studied. The median delta FEV1 after a single dose of AP was -7.0 percent (range: -47 percent, 1.8 percent). The delta FEV1 following AP was only partially predicted by the degree of nonspecific bronchial responsiveness as measured by a standard methacholine challenge. Age, current smoking, history of asthma, baseline FEV1, or a prior episode of PCP failed to predict the delta FEV1 following AP. Eighteen subjects (34 percent) had a delta FEV1 greater than or equal to 10 percent decrease (median: -17.0 percent). In these subjects, after premedication with salbutamol, ipratropium bromide, and sodium cromoglycate, the median delta FEV1 was 1.0, 0.8, and -9.6 percent, respectively. CONCLUSION: Aerosol pentamidine produced a decrease in FEV1 greater than or equal to 10 percent in 34 percent of subjects. This was not accurately predicted by the methacholine response. The bronchoconstriction induced by AP was effectively prevented by either salbutamol or ipratropium, whereas cromoglycate was only partially effective.

Canadian multicenter azidothymidine trial: AZT pharmacokinetics.

The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HIV)-infected individuals. The study design was a multicenter, prospective, descriptive single-dose pharmacokinetic study. Each of 66 fasting, male, HIV-infected homosexuals older than 18 years of age and in CDC classifications II, III, and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite, glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers, 29 nonsmokers), of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function, the following parameters were described: AZT, area under the curve (AUC) +/- SD, 9.9 +/- 5.7 microM.h, maximum concentration (Cmax) +/- SD, 7.3 +/- 4.7 microM; time to maximum concentration (Tmax) +/- SD, 0.93 +/- 0.42 h, and half-life (t1/2) +/- SD, 1.0 +/- 0.8 h. Corresponding values for GAZT were: AUC +/- SD 35.7 +/- 10.3 microM.h, Cmax +/- SD 21.3 +/- 7.3 microM, Tmax +/- SD 1.2 +/- 0.50 h, t1/2 +/- SD 0.98 +/- 0.62 h, No significant differences were found in comparisons of study site, CDC classification of disease, smokers versus nonsmokers, and in patients with hepatic dysfunction, although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomatic HIV disease when compared with previous reports in patients with later disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical significance and characterization of AZT-resistant strains of HIV-1.

A number of laboratories have now independently confirmed that zidovudine (AZT)-resistant strains of human immunodeficiency virus type 1 (HIV-1) may be isolated from patients undergoing prolonged therapy with this drug. In certain instances, such drug-resistant viral isolates have been obtained from patients with clinical acquired immune deficiency syndrome (aids), while in others, isolation of drug-resistant strains has been achieved in the case of HIV seropositive, asymptomatic subjects. Most of the evidence points to a series of mutations within the polymerase gene of HIV-1, which encodes viral reverse transcriptase, as being responsible for development of the drug-resistant phenotype. It further appears that over 50% of patients treated with AZT for periods longer than six months are likely to yield drug-resistant strains of HIV-1 in their circulation. Furthermore, the development of drug resistance soon after initiation of AZT therapy may potentially be correlated with the likelihood of AZT treatment failure. In several instances, cross resistance has been observed between AZT and other nucleosides being considered for potential therapy of HIV-1-associated disease.

Pathologic dependence of oxygen consumption on oxygen delivery in acute respiratory failure secondary to AIDS-related Pneumocystis carinii pneumonia.

Oxygen consumption is pathologically dependent on oxygen delivery in ARDS and sepsis. We asked whether oxygen consumption is dependent on oxygen delivery in severe acute respiratory failure secondary to AIDS-related PCP. In five patients who had AIDS-related PCP, diffuse bilateral pulmonary infiltrates, no evidence of bacterial infection, and acute respiratory failure requiring mechanical ventilation with arterial oxygen tensions less than 75 mm Hg while breathing at least 50 percent oxygen, and PEEP greater than 10 cm H2O, we determined oxygen delivery and consumption by calculation from thermodilution cardiac output and arterial and mixed venous oxygen contents. Oxygen delivery was increased using transfusion of two units of packed red blood cells over one hour. Oxygen delivery increased 22 percent (638 +/- 204 to 778 +/- 201 ml/min.m2, p less than or equal to 0.006). Oxygen consumption increased 11 percent (134 +/- 34 to 149 +/- 29 ml/min.m2, p less than or equal to 0.02). The oxygen extraction ratio did not change. We conclude that similar to ARDS and sepsis, oxygen consumption may be pathologically dependent on oxygen delivery in patients who have severe acute respiratory failure secondary to AIDS-related PCP.

Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS)

OBJECTIVE: To determine whether oral corticosteroids can prevent early deterioration in patients with acquired immunodeficiency syndrome (AIDS)-related Pneumocystis carinii pneumonia. DESIGN: Prospective, double-blind, placebo-controlled, randomized trial. METHODS: Included patients were having their first P. carinii pneumonia episode, had no other known active pulmonary pathology, had no contraindications for corticosteroids, received no anti-P. carinii pneumonia medications for more than 48 hours, and had oxygen saturation by pulse oximetry of 85% or more and less than 90% at rest or a 5-percentage-point decrease in oxygen saturation with exercise while breathing room air. Consenting subjects were randomly assigned to prednisone, 60 mg/d for 7 days, followed by a progressive tapering over 14 days or to an identical placebo. Early deterioration, the endpoint of the trial, was defined as a 10% decrease in baseline oxygen saturation on day 3 or thereafter. The cases of patients developing early deterioration were considered to be failures of treatment; the code was then broken, and the patient's treatment was left to the judgment of the treating physician. Sequential analysis was done with the primary variable being development of early deterioration. RESULTS: The trial was terminated 5 April 1989 on the basis of the sequential analysis when a total of nine episodes of early deterioration had occurred in the first 37 patients at an overall significance level of P = 0.0136. A total of 8 of 19 placebo-treated patients (42.1%) developed early deterioration compared with only 1 of 18 patients (5.6%) treated with corticosteroids. Baseline characteristics were not statistically different between the two treatment groups. The adjusted odds ratio for the treatment effect was 5.87 (95% CI, 1.27 to 27.4). The adjusted point estimates for the probability of early deterioration in the placebo and corticosteroid groups were 43% and 12%, respectively. All 8 patients in the placebo group developing early deterioration recovered rapidly with addition of corticosteroid treatment. The single patient with early deterioration in the corticosteroid group died on day 6 from overwhelming P. carinii pneumonia, as documented at autopsy. The corticosteroid group had an increased exercise tolerance on day 7 that persisted at day 30. CONCLUSION: Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with moderately severe AIDS-related P. carinii pneumonia.