A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir).

OBJECTIVE: To investigate the safety, pharmacokinetics, and activity of the orally bio-available protease inhibitor MK-639. DESIGN: An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts < or = 300 x 10(6)/I and > or = 20,000 HIV RNA copies/ml. Pharmacokinetics were performed at days 1 and 15. In order to better understand the relationships between drug exposure, baseline activity markers, and their changes during the study, mathematical modeling was performed using the traditional sigmoid-Emax relationship of pharmacologic effect and first order inhomogeneous differential equations for a two compartment system. RESULTS: The five men enrolled had extensive prior nucleoside therapy (mean, 32.6 +/- 25.6 months), a low mean CD4 lymphocyte cell count (CD4 count, 66.1 +/- 61 x 10(6)/I and CD4 percentage, 4.4 +/- 3.1%), high soluble tumor necrosis factor-alpha type II (sTNFII) receptor concentration (6.23 +/- 2.76 ng/ml) and high viral load (5.13 +/- 0.46 log10 RNA copies/ ml; geometric mean, 133,941 copies/ml). The drug was well tolerated at a dose of 600 mg every 6 h. The steady state concentrations Cmax and Cmin were 4.94 +/- 2.16 microM and 0.28 +/-0.1 microM, respectively, which are approximately equal to 50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143 x 10(6)/ (217% increase ), the mean increase in CD4 percentage was 5.2 percentage points (118%), mean decrease in HIV RNA was 1.55 log10 RNA copies/ml (a geometric mean difference of 130,120 copies/ml or 97% decrease) with a slow upward drift on continued therapy to a mean 0.64 log10 RNA copies/ml decrease by week 24 (a geometric mean difference of 103,084 copies/ml or 77% decrease), and a mean decrease in sTNFII receptors of 2.78 ng/ml (45% decrease). The mean CD4 counts per week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2 = 0.998, P < 0.0001) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. Drug exposure as measured by either the total exposure (area under the concentration/time curve) or as the Cmin gave similar significant relationships to the fractional inhibition of HIV generation (r2 = 0.999, P < 0.0001, and r2 = 0.996, P < 0.0001, respectively). CONCLUSIONS: MK-639 appears to have significant dose-related antiviral activity and is well tolerated.

Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients.

Through a retrospective review, we identified 77 previously unreported cases of coccidioidomycosis during HIV infection. Patients were classified into 1 of 6 categories based on their primary clinical presentation: 20 had focal pulmonary disease (Group 1), 31 had diffuse pulmonary disease (Group 2), 4 had cutaneous coccidioidomycosis (Group 3), 9 had meningitis (Group 4), 7 had extrathoracic lymph node or liver involvement (Group 5), and 6 has positive coccidioidal serology without a clinical focus of infection (Group 6). Coccidioidal serologies were positive on initial testing in 83% of the patients in whom such serologic testing was performed. Sera from 39% of patients were positive for TP antibodies while 74% had CF antibodies. Eleven of 12 seronegative patients had pulmonary disease (Group 1 or 2). Serologic results of other patients sent to a single reference laboratory were similar, with 26% positive for immunodiffusion TP antibodies and 79% positive for immunodiffusion CF antibodies. For the 77 patients in this study, the CD4-lymphocyte count was below 0.250 X 10(9) cells/L in 46 of the 55 patients who had this test performed, and a low CD4 count was significantly associated with mortality (p less than 0.01). At the time of follow-up, 32 of the 77 patients (42%) had died. There were significantly more deaths in those with diffuse pulmonary disease (Group 2) than in other groups (p less than 0.001). Amphotericin B, ketoconazole, fluconazole, and itraconazole were all used as antifungal therapies. Outcome could not be related to the therapy used. Of note, 3 patients developed coccidioidomycosis while receiving ketoconazole for other conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

The professional objectives of canadian dental students.

Data from a 1971 national study of Canadian dental education are used as a basis for examining the relative importance which dental students and faculty place on the professional objectives of economic gain and service. Students (N = 1,247) were asked to rank a set of career attributes in terms of their importance both for themselves and for other students. Dental school faculty (N = 510) were asked to assess whether students under emphasized or overemphasized a group of 16 parallel objectives. The results indicate substantial variations between the professional objectives of individual students, those ascribed to others by students, and the faculty's perception of student objectives.

Tuberculosis status and social adaptation of Indochinese refugees.

The relationship between tuberculosis and social adaptation of Indochinese refugees in Manitoba, Canada, is examined in 43 randomly selected refugees treated for active and inactive tuberculosis (cases) and their matched controls. Tuberculosis status did not significantly affect adaptation as measured by selected scales and indicators. Significant predictors of better personal well-being included a low number of family members outside the household in Manitoba, non-use of traditional medicine, female gender, and high individual income. Tuberculosis status was not a significant predictor.

The resident's view of residency training in Canada.

In the view of residents in their last year of specialty training, the Fellowship is now becoming the operative standard for obtaining hospital privileges in urban centres and they felt that this implied that the two standards, the Certificate and the Fellowship of the Royal College, were not achieving the purpose for which they were designed. Although 80% of the residents intended to write the Fellowship, few viewed a year in a basic science department or in research as of intrinsic value in terms of their future practice.The examinations of the Royal College were the subject of criticism, most residents feeling that the examinations did not test the knowledge and ability gained in training. Most expressed a desire for ongoing evaluation during the training period.Service responsibilities were generally regarded as too heavy.Despite the criticism of both training and examination, most residents felt that their training had provided them with the experience and background they needed to practise as specialists.

Career and training patterns of students entering Canadian medical schools in 1965.

This paper follows the careers of the 1128 students who entered Canadian medical schools in 1965, most of whom graduated in 1969. The type of career pursued (whether general or specialty practice or some combination thereof), the type of specialty undertaken, the place of internship and residency training and the 1973 practice location of the graduates are examined. The wide variation in careers followed by the 12 schools' graduates provides the major focus of the paper.

Canadian-trained physicians in United States internships and residencies: "Operation Retrieval" and Report of Statistics, 1966-1968.

In response to a shortage of medical teachers and scientists, A.C.M.C. began "Operation Retrieval" in 1967 in an effort to contact and to survey graduates of Canadian medical schools who are interns and residents in the United States. This paper describes the publications produced for these graduates, and the concerns of graduates as discovered by on-site visits to Los Angeles, Boston and New York. These concerns centre around difficulties in communication with Canada. This paper also gives a statistical report on the numbers of graduates who are interns and residents in the United States, and the locations, fields of specialization and years of graduation of residents. The decreasing numbers are believed to reflect improving Canadian facilities as well as difficulties associated with the American military draft.

Career preferences of first-year students at Canadian medical schools, 1966-67 to 1968-69.

The principal findings of this study of the career preferences of first-year Canadian medical students were:Over 70% of the first-year students expressed a preference for specialty practice, with only 20% oriented towards practice as a family practitioner.There were considerable differences between the medical schools in the proportion of medical students preferring general practice, ranging from less than 10% at McGill to nearly 33% at Queen's.Nearly one-third of the students stated that they preferred primarily salaried practice. These students were largely those who preferred specialty practice or a career in an area such as public health or research.Nearly 70% of the students looked for a career with part-time teaching, while 8% preferred a full-time teaching career.Only 1% preferred a full-time research career although 90% expected to have at least some research involvement.Students from smaller communities were more likely to express a preference for general practice than those from large urban areas.Men and women had similar practice preferences in terms of general practice and clinical specialty, but significantly more women than men preferred a career in salaried practice. Significantly fewer women expressed a preference for major involvement in either teaching or research.

Canadian and landed immigrant applicants to Canadian medical schools for 1968-69.

There were 2337 Canadian and Landed Immigrant applicants for the fall 1968 entering classes at Canadian medical schools. These applicants filed a total of 4579 applications.The results of this study show that there are regional differences in the quantity and quality of the applicant pool for Canadian medical schools. The study also shows that despite the fact that Canadian and landed immigrant applicants are filing more applications than they have in the past two years, there has been no appreciable change in the ratio of applicants to available places. A further point to be noted is that the participation of women both as applicants to and as medical students in the entering class of 1968-69 at Canadian medical schools was higher than in previous years.

Projections of graduates from Canadian medical schools, 1970-81.

This paper sets forth the projections made by the various Canadian medical schools of first-year undergraduate enrolment through 1977-78. Non-Canadian enrolment and student attrition are discussed and some assumptions are made concerning their levels up to 1981. In conclusion, a set of projections on Canadian and landed immigrant graduates from Canadian medical schools during the period 1970-1981 is offered. The national projections are broken down by medical school and province.The results of this paper indicate that Canadian medical schools will graduate 1019 Canadians and landed immigrants in 1970, 1052 in 1971, 1064 in 1972, 1113 in 1973, 1250 in 1974, 1342 in 1975, 1377 in 1976 and 1480 in 1981.

Medical education. I. Medical students in Canadian Universities: report of statistics, 1966-67.

Enrolment in the 13 Canadian medical schools in 1966-67 reached a new high of 4230, an increase of 5.1% over 1965-66. The percentage of women among medical students (12.1%) was close to that of the preceding three years. There has been a levelling off in the decline of students from outside Canada in 1966-67, when 9.5% of medical students were non-Canadian. The decline had been primarily in the number of American students, which continues. The number of students from Commonwealth countries has shown a steady increase during the eight-year period under review; in 1966-67, they make up nearly one-half of all non-Canadian students. It was noted that 18.5% of overseas students came to Canada under governmental or intergovernmental sponsorship. Of the Canadian students, 94% came from the "home" provinces of the medical schools.

Applicants to Canadian medical schools for 1966-67.

An examination of applicants to Canadian medical schools for 1966-67 revealed that 4534 applications were received for the approximately 974 available places. The number of Canadian applications was 2866 and these were made by 1815 individual applicants, an increase of 48 over 1965-66. United States applicants declined from 1143 to 1013.Evaluations made by the schools concerning the acceptability of the Canadian applicants disclosed that 55 applicants who rated as "acceptable" by one or more schools failed to gain admission to any medical school in 1966-67 (as compared to 36 in 1965-66). However, of those applicants who did find a place 76 were evaluated as "marginal" or "unacceptable", while another 126 were rated as "acceptable" by one school but "marginal" and/or "acceptable" by one or more other schools.These results were interpreted to imply that the Canadian medical schools were still experiencing difficulty in attracting well-qualified applicants for study in medicine.

The premedical education of the first-year class in Canadian medical schools: 1965-66.

The premedical academic records of the 1965-66 entering class of Canadian medical students were analysed. Ninety-six per cent of the class had taken their preparation in a Canadian institution, while 80% had taken it in the same university as the medical school in which they enrolled. Forty per cent entered without a degree, the remainder having at least a bachelor's degree in arts or science.Thirty-six per cent of all courses taken by these students in their premedical education were in the physical sciences, 22% in the biological sciences and 41% in the social sciences and humanities. One-third of the students had taken no course in the behavioural sciences and another third had taken only one course.Analysis of the level of performance of the entering class showed that 10% had obtained an A average, 49% a B average, 41% a C average and 3% a D average. The grades of these students were higher generally in the natural sciences than in the social sciences or humanities.It was concluded that it could be questioned whether medical students received a premedical preparation which met the philosophy of a "broad, liberal education".

Canadian-trained basic medical scientists, 1946-47-1963-64.

The number of master's and doctoral degree holders who obtained their degree in a basic medical science under the supervision of a Canadian medical faculty between 1946-47 and 1963-64 was obtained from the medical schools. Of the total degree holders, 69% are currently residing in Canada, 23% in the U.S.A., and the remaining 8% in overseas countries.Questionnaire returns from doctoral degree holders revealed that citizenship status at the time of graduation is positively related to migration; migration rates were lowest for Canadian-born and highest for landed immigrants and foreign students. Geographic mobility during training was also found to be a significant factor which increased the propensity to migrate. One-half of those who took further postdoctorate training in the United States are currently living in the United States, compared to 15% of those who received all their training in Canada. Information on current type of employment revealed that only a quarter of the Ph.D. respondents are in a basic science teaching position in Canada.

A comparison of applicants and applications to Canadian medical and dental schools, 1965-66.

A collation and analysis of the applications and applicants to Canadian medical and dental schools for 1965-66 showed that the ratio of applications to the number of places available was 5.3 to 1 for medical schools, and 4.7 to 1 for dental schools.Sixty-seven per cent of the Canadians who applied to a dental school did not find a place, in contrast to the 47% of those who applied to a medical school and were not successful.One hundred and forty-one applicants (4.3% of the total applicants to medical schools and 10.9% of total applicants to dental schools) had applied to both medical and dental schools. Almost 50% of these "dual applicants" were not accepted by either a medical or dental school. Thirty-five applicants were accepted at both dental and medical schools and all but three of these elected to enrol at a medical school.

Canadian-trained medical scientists view Canadian academia from their American laboratories.

Interviews with 98 Canadian-trained basic medical scientists currently employed in the United States reveal that they were attracted to the United States by the belief that greater career opportunities exist in the United States than in Canada.THEY ATTRIBUTED THE FAILURE ON THE PART OF CANADA TO ATTRACT SCIENTISTS TO CANADA AND TO RETAIN THEIR OWN GRADUATES TO: (1) Poor recruiting methods and a failure on the part of Canadian employees to keep in touch with Canadian scientists in American graduate and postgraduate training positions. (2) Scarcity of research funds. (3) Lack of opportunity in Canada occasioned by the smaller number of medical schools and medical research institutions as compared to the United States. (4) The negative conservatism of Canadian academic circles occasioned by academic inbreeding, anti-Semitism, Anglophilia and the tight control of research, research funds and university appointments by an oldguard "establishment".

Canadian medical student interest in general practice and the specialties.

The interest of 1900 Canadian medical students in the various fields of medical practice was measured by a questionnaire. The students were asked to rank the various fields in order of their interest in them. It was found that general practice, internal medicine and surgery were the fields which consistently captured most interest among the students. Few students ranked dermatology, administration, teaching and research in the first three ranks.Striking differences in the interest preferences of male and female students were demonstrated, with the women ranking pediatrics and psychiatry higher than the men. Significantly more men, however, expressed a prime interest in surgery.Interest in general practice increases with the senior years in medical school, but it was shown that this increase is associated with marital status and with the number of children rather than with the year of training alone.Interest in the fields of medical practice varied between medical schools, with general practice ranking highest at British Columbia and relatively low at McGill and Manitoba. Significant differences between the students of the schools were displayed in the case of neurology, obstetrics, pediatrics and psychiatry.