Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

BACKGROUND: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? AIMS: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. METHODS: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator's early life educational history in order to predict the innovator's likely success at medical school entry, assuming excellence in all entrance requirements. RESULTS: Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today's standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. CONCLUSION: These data show that today's medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

Bacteremic Haemophilus influenzae genitourinary tract infections in adults.

Six cases of bacteremia associated with genitourinary (GU) tract infections in adults due to Haemophilus influenzae occurred during a 42-month period at the Health Sciences Centre in Winnipeg, Canada. Four cases were associated with pregnancy or abortion, one with acute salpingitis, and one with urinary tract manipulation. Four of the five strains available for serotyping were nontypable. Clinical conjunctivitis was present in one patient, and infants born to two other patients developed purulent conjunctivitis from which H influenzae was grown. These six cases, and others from the literature, include a wide spectrum of GU tract infections due to this organism. With the rising incidence of severe infections in adults due to this organism, and the widespread emergence of ampicillin-resistant strains, H influenzae must be considered a GU tract pathogen.

Trimethoprim alone in the treatment and prophylaxis of urinary tract infection.

Trimethoprim was used alone to treat urinary tract infections in 20 women who were unable to tolerate sulfonamides. Of ten acute symptomatic urinary tract infections, four were cured, three were not, and three cases could not be evaluated. Two other women received trimethoprim for suppression of infection complicating stag-horn calculi. The conditions of both patients improved clinically but the urine remained infected. Eight women treated prophylactically with low-dose trimethoprim for recurrent urinary tract infection accumulated a total of 16 patient-years of prophylaxis. During treatment, the incidence of infection was 0.56 per patient-year compared with 4.25 infections in the year preceding study. Adverse reactions occurred in eight of 20 patients and administration of the drug had to be stopped in five cases. Trimethoprim alone is effective for the treatment and prophylaxis of urinary tract infections, but may cause a high incidence of adverse reactions in patients known to be sensitive to sulfonamides.

Genital ulceration as a risk factor for human immunodeficiency virus infection.

Among 115 heterosexual men who presented with genital ulcers to a sexually transmitted disease clinic in Nairobi, Kenya, the prevalence of serum antibody to HIV was 16.5%. A past history of genital ulcers was reported by 12 (63%) of 19 men with antibody to HIV versus 30 (31%) of 96 without antibody (P = 0.008). HIV infection was also positively associated with lack of circumcision, but was not associated with the etiology of the current genital ulcer. Logistic regression analysis (adjusted for age, number of recent sex partners, recent prostitute contact, circumcision, tribal ethnic identity, past history of urethritis, and current diagnoses) confirmed only the association between prior history of genital ulcer disease and HIV infection; (P = 0.04, odds ratio 2.35, 95% confidence limits, 1.01-5.47). The incidence of genital ulcers, particularly chancroid, is much higher in parts of Africa than in Europe or North America. This may contribute to the increased risk of heterosexual transmission of HIV in Africa. Aggressive control of chancroid and syphilis may offer one very feasible approach to reducing transmission of HIV in this region.

Seroprevalence and demographic information of patients at risk for human immunodeficiency virus (HIV) infection in Manitoba, Canada.

Two hundred fifty individuals from high risk categories were enrolled in a seroprevalence survey for human immunodeficiency virus (HIV) infections in Winnipeg. The overall seroprevalence in the Manitoba AIDS Virus Epidemiology Study (MAVES) was 5.2%. Of 2651 diagnostic and screening specimens in the province of Manitoba submitted over a similar period, 103 were positive (3.9%). HIV seropositivity in Manitoba was noted mainly in homosexual/bisexual males (especially those who were also intravenous drug abusers), hemophiliacs, and individuals from endemic regions of the world. Individuals whose only risk factor was intravenous drug abuse, those with sexually transmitted diseases, or those with high risk sex contacts have not demonstrated HIV seropositivity in Manitoba to date. Manitoba is currently a low seroprevalence region for HIV infection. Our study demonstrated that the awareness level of people at risk for HIV infections was low. In our study population, one-on-one counseling was demonstrated to be an effective way to improve short-term knowledge about HIV infections. Appropriate education approaches must be considered for Native/Metis peoples (26.4% of our MAVES study population), who were younger and had a lower educational and employment level compared to Caucasian/other racial groups.

Norfloxacin: its potential in clinical practice.

The in vitro spectrum and potency of norfloxacin against both aerobic gram-negative and gram-positive bacteria, its limited activity against anaerobes, and the apparent difficulty organisms have in acquiring resistance to it, have provided a rationale for the clinical development of this oral fluoroquinolone antimicrobial agent. The clinical experience with norfloxacin as treatment for a variety of urinary tract infection syndromes, uncomplicated gonococcal infection, and diarrheal disease, and as prophylaxis of infection in neutropenic patients with cancer, is reviewed. Norfloxacin appears at least equivalent to standard regimens for the treatment of acute urinary tract infections; however, long-term studies are needed to define its role in the treatment of recurrent urinary infections. Initial studies of norfloxacin treatment of uncomplicated gonococcal infection and bacterial gastroenteritis are also promising, and in neutropenic patients, continuous norfloxacin prophylaxis has been shown to reduce the incidence of gram-negative infections. Further prospective evaluation is required to confirm these findings.

Cerebrospinal fluid as a diagnostic body fluid.

The cerebrospinal fluid is a dynamic, metabolically active substance that has many important functions. It is invaluable as a diagnostic aid in the evaluation of inflammatory conditions, infectious or noninfectious, involving the brain, spinal cord, and meninges. The cerebrospinal fluid may be obtained with relative ease with the use of lumbar puncture, but failing this, alternative techniques are available. With the judicious use of the computerized axial tomographic scan, the removal of cerebrospinal fluid has little attendant risk. Age-related and compartmental variations in chemical and cellular composition are important considerations in the interpretation of results. Alterations in cerebrospinal fluid constituents from different pathologic processes may be similar in certain circumstances and cause interpretation difficulties.

Advances in the treatment of urinary tract infection.

Single dose treatment regimens are currently the treatment of choice in women with acute urethrocystitis. Women who have concomitant asymptomatic renal infections will have a recurrence and require further investigation and more conventional 14-day treatment regimens. Single dose treatment is a specific and moderately sensitive diagnostic aid for women with urinary infection. Further carefully planned studies are required to determine optimal treatment regimens for women with renal infection and men with infections originating in the kidneys or prostate.

A prospective controlled investigation of prophylactic trimethoprim/sulfamethoxazole in hospitalized granulocytopenic patients.

Oral trimethoprim/sulfamethoxazole (TMP/SMZ) therapy was investigated in the prophylaxis of infections in granulocytopenia. Hospitalized granulocytopenic patients were allocated at random to receive TMP/SMZ (group 1) or to a control group (group 2). The percentage of febrile granulocytopenic days was significantly reduced in group 1, 19 per cent compared to 39 per cent in group 2 (P less than 0.01). In group 1, there were no bacteremias in 59 episodes of granulocytopenia (909 days). In group 2, there were nine bacteremias in 52 episodes of granulocytopenia (796 days)(P = 0.001). Disseminated candidiasis developed in two patients in each group. Candida occurred in similar numbers in surveillance cultures in both groups; Staphylococcus aureus and Pseudomonas aeruginosa were slightly decreased, and Enterobacteriaceae resistant to TMP slightly increased in group 1. This study suggest that oral prophylactic TMP/SMZ therapy is an effective, well tolerated, easily administered alternative to "gut sterilization" with nonabsorbable antibiotics.

Granulocytopenia in hospitalized patients: I. Prognostic factors and etiology of fever.

The clinical course of 126 hospitalized patients during 192 episodes of granulocytopenia and fever was studied. Fever was a regular accompaniment of granulocytopenia, occurring in 94 per cent of granulocytopenic episodes. The mean duration of granulocytopenia (less than 1,000/mm3) was 18 days, with fever (temperature greater than 38 degrees C) being present during 44 per cent of those days. Fever was present during 69 per cent of days with a granulocyte count less than 10/mm3. A presumed infection was present in 86 of 128 febrile granulocytopenic episodes in adults and in 19 of 64 febrile granulocytopenic episodes in children. A fungal infection was found in 11 patients; a viral infection in 23 patients. Bacteremia occurred during 44 granulocytopenic episodes with 16.8 bacteremias/1,000 days of granulocytopenia in adults and 12.7 bacteremias/1,000 days in children. The mortality was 33 per cent per granulocytopenic episode in adults and only 8 per cent per episode in children.

Granulocytopenia in hospitalized patients. II. A prospective comparison of two antibiotic regimens in the empiric therapy of febrile patients.

The results of empiric antibiotic therapy in 126 hospitalized patients with fever during 192 episodes of granulocytopenia were studied. Febrile granulocytopenic patients were randomly allocated to receive either carbenicillin, methicillin and gentamicin, or carbenicillin and cephalothin. The response rate for the two antibiotic regimens was similar, 49 (60 per cent) of 81 responded to the former and 42 (54 per cent) of 78 to the latter. The response rate in patients receiving other antibiotics because of specific indications or counterindications was 19 (58 per cent) of 33. Thirty-nine (35 per cent) of 110 patients who responded to initial antibiotic therapy had an increase in circulating granulocytes of one log10 or more compared to only 10 (12 per cent) of 79 nonresponders with such an increase. The mortality rate in adult patients receiving carbenicillin, methicillin and gentamicin was eight (16 per cent) of 51, compared to 18 (37 per cent) of 49 in those receiving cephalothin and carbenicillin (P less than 0.05). The significance of this difference in the initial response rate or mortality rate between patients treated with the two antibiotic regimens when only patients with documented bacterial infection were considered. Patients who responded to their initial antibiotic regimen, and patients for whose fever no explanation was found, had the best prognosis.

Treatment of chancroid with ciprofloxacin. A prospective, randomized clinical trial.

Chancroid is a major sexually transmitted disease in many developing countries. Although single-dose and short-course treatment of chancroid have been described, the increasing resistance of Hemophilus ducreyi to antimicrobial agents requires continuing evaluation of new therapies. Ciprofloxacin is a new quinolone antimicrobial agent with excellent in vitro efficacy against H. ducreyi. A double-blind, randomized clinical trial was conducted comparing a single-dose ciprofloxacin regimen (500 mg) and a three-day regimen of ciprofloxacin (500 mg twice daily) with a three-day regimen of trimethoprim-sulfamethoxazole (160 and 800 mg, respectively, twice daily) for the treatment of chancroid. The three-day ciprofloxacin regimen successfully eradicated H. ducreyi, and resulted in rapid clinical improvement in all 40 patients followed, with no failures. The other two regimens were also effective, but bacteriologic and clinical failure occurred in two and three patients following treatment with single-dose ciprofloxacin and three days of trimethoprim-sulfamethoxazole, respectively. All patients with buboes had resolution of lesions. There were no significant adverse effects associated with ciprofloxacin or trimethoprim-sulfamethoxazole. All three regimens are effective therapy for chancroid and H. ducreyi infections. If resistance to trimethoprim-sulfamethoxazole becomes widespread, ciprofloxacin may become a first-line therapy for chancroid. This study also demonstrates the efficacy of ciprofloxacin in soft tissue infection.

Fleroxacin in the treatment of chancroid: an open study in men seropositive or seronegative for the human immunodeficiency virus type 1.

Fleroxacin was prescribed to treat both HIV-negative and HIV-positive men with proven chancroid in an open study. HIV-negative men were treated with a single 400-mg dose of fleroxacin, and HIV-positive men were treated with 400 mg daily for 5 days. Three of the 58 evaluable HIV-negative men were clinical and microbiologic failures, and two of the 22 evaluable HIV-positive men had persisting infection with Haemophilus ducreyi. Both regimens were well tolerated. Fleroxacin is an acceptable alternative to existing treatment regimens for chancroid in men.

Randomized controlled trial comparing trimethoprim/sulfamethoxazole and trimethoprim for infection prophylaxis in hospitalized granulocytopenic patients.

The clinical and microbiologic efficacy of trimethoprim alone and trimethoprim/sulfamethoxazole for infection prevention was evaluated in 75 patients during 92 episodes of granulocytopenia. Ultimately, 60 patients were evaluable during 77 episodes of granulocytopenia, 36 episodes in the trimethoprim group and 41 episodes in the trimethoprim/sulfamethoxazole group. The incidence of infection was higher in the trimethoprim group (50 percent) than in the trimethoprim/sulfamethoxazole group (39 percent), but this did not reach statistical significance. Trimethoprim did not appear to be as protective as trimethoprim/sulfamethoxazole when the granulocyte count was less than 100/mm3. In patients receiving trimethoprim/sulfamethoxazole, aerobic gram-negative bacilli cleared from fecal surveillance cultures more often and new aerobic gram-negative bacilli were acquired less often than in those receiving trimethoprim alone (p less than 0.05). More myelosuppression was observed among patients receiving trimethoprim/sulfamethoxazole (p less than 0.001). These observations suggest that trimethoprim alone may not be optimal for preventing colonization and infection in granulocytopenic patients and that combination with other agents may be necessary to increase the spectrum of activity. Trimethoprim/sulfamethoxazole itself may predispose toward an increased risk of infection by prolonging myelosuppression.

Geographical patterns of male circumcision practices in Africa: association with HIV seroprevalence.

To ascertain whether male circumcision might explain some of the geographical variation in human immunodeficiency virus (HIV) seroprevalence in Africa, we investigated the association between the practice of male circumcision at a societal level and HIV seroprevalence. Male circumcision practices for over 700 African societies were identified, and HIV seroprevalence in general adult populations from 140 distinct locations in 41 countries was obtained. In locations where male circumcision is practised, HIV seroprevalence was considerably lower than in areas where it is not practised. This study supports the hypothesis that lack of circumcision in males is a risk factor for HIV transmission.

Slowing heterosexual HIV transmission.

HIV-1 is spreading rapidly through heterosexual intercourse in many societies. Slowing the transmission of this virus is the most urgent global public health priority. Our understanding of the biologic differences between societies that account for most vacancies in heterosexual HIV transmission are now understood. Effective interventions to slow transmission must be designed, implemented, and evaluated. Human and fiscal resources must be provided through a shared global effort. The consequences of failing to do so will lead to a world catastrophe of unprecedented magnitude.

PIP: Of the approximately 15 million HIV infections that have occurred since the epidemic began, over 10 million have been transmitted heterosexually. Although there have been studies to show that HIV-1 is relatively inefficiently transmitted heterosexually and substantially less readily transmitted than is herpes simplex 2 virus or human papilloma virus, studies in Kenya have identified 5 factors that facilitate heterosexual spread of HIV-1: 1) promiscuity, 2) other sexually transmitted diseases (ulcers, particularly chancroid), 3) cervical ectopia, 4) uncircumcised men, and 5) increased titers of HIV-1 secreted in the genital secretions of immunosuppressed patients. Poverty, illiteracy, discrimination and stigmatization, gender inequality, low respect for human rights, and political and civil unrest are also underlying determinants of HIV epidemiology. The World Health Organization Global Program on AIDS has mobilized resources to control AIDS, but culturally inappropriate interventions can be detrimental to slowing and stopping the spread of HIV-1. HIV prevention is difficult because of the stigmatization associated with it, the long incubation period negates awareness of cause and effect, and sexual behavior is poorly understood in all societies. Specific interventions comprise: 1) a defined mission with strong links to the national head of state and annual review of the program goals and strategies; 2) mass media and targeted educational campaigns to increase public awareness of AIDS and encourage behavior change; and 3) the synergism between HIV and other sexually transmitted diseases provides an opportunity for targeted interventions. Among specific interventions are: 1) Behavioral interventions for vulnerable groups. In Thailand condom promotion, prostitute and brothel registration, and education of those in male risk groups resulted in a 70% reduction in cases of STDs. 2) Improved clinical services for sexually transmitted infections. 3) Research to understand sexual health. 4) Integration of HIV- and STD-control programs. Physical and chemical barriers should be the major strategy of reduction and prevention of HIV transmission.

Recurrent urinary tract infection in adult women: diagnosis and treatment.

Recurrent urinary infection may be either relapse or reinfection. The majority of women experiencing recurrent infection have normal genitourinary tracts. For recurrent cystitis, single-dose therapy is optimal and symptomatic episodes are effectively prevented with continuous low-dose antimicrobial prophylaxis. For upper tract infection, or relapse after single dose therapy, two-week therapy is generally adequate. Investigation for abnormalities of the genitourinary tract should be reserved for women who fail to respond to therapy or with relapsing or bacteremic infection.

Complicated urinary tract infections.

Urinary infections complicated by structural anomalies, metabolic alterations, abnormalities of host response, or unusual or difficult-to-treat pathogens commonly occur in our practices. Therapeutic regimens for most of these patient populations are empiric and unproven. Our understanding of specific microbial virulence factors is inadequate. Until well-designed interventions are proven, management strategies will depend on clinical biases and "trial and error" therapeutic attempts. Presumably, over the course of the next decade, better answers will emerge that will improve our ability to prevent and more adequately manage our patients with complicated UTIs.

Relationship between lipopolysaccharide composition and virulence of Haemophilus ducreyi.

The relationship between lipopolysaccharide (LPS) composition and virulence of Haemophilus ducreyi strains was investigated. Glycoses identified in LPS by gas-liquid chromatography were glucose, galactose, and their amino derivatives glucosamine and galactosamine. Fucose was found in trace amounts but mannose and rhamnose, characteristic of the O-side chain of LPS in many species, were not detected. Qualitatively, the LPS composition of the eight strains examined was similar and differences were mainly quantitative. The total glycose:KDO ratio of the LPS of virulent strains exceeded that of avirulent strains. All strains had similar fatty-acid composition but lacked lauric acid. SDS-polyacrylamide gel electrophoresis of the LPS of virulent and avirulent strains also revealed differences in their electrophoretic mobilities. The LPS profiles of avirulent strains were similar, but differed from those of virulent strains. These profiles lacked high mol. wt bands representing O-side chain repeating units. Thus, differences in the electrophoretic mobilities of the LPS of virulent and avirulent strains may reflect differences in the amount of carbohydrates associated with the core polysaccharide.

Isolation and identification of Haemophilus ducreyi in a clinical laboratory.

Routine procedures used to isolate Haemophilus ducreyi in a busy laboratory are reported. Identification was based on colony morphology and nutritional and biochemical properties of 120 fresh isolates of H. ducreyi. These isolates grew very well on Gonococcal Agar and Mueller-Hinton Agar incubated at 34 degrees C in candle extinction jars containing moistened filter paper. Colonies varied in size, giving a polymorphic appearance. They were smooth, dome-shaped, and buff-yellow to grey in colour, and measured 2 mm in diameter. They could be pushed intact across the agar surface. By microscopic examination of gram-stained smears the isolates were gram-negative coccobacilli arranged in short chains, clumps or whorls and occasionally in typical "rail track" arrangements. Individual bacteria showed bipolar staining. Colonies autoagglutinated in saline. All strains were catalase-negative and did not produce indole or H2S. They were oxidase- and beta-lactamase positive and required X but not V factor for growth. Now that reliable techniques have been developed and characteristics established it is possible for most clinical laboratories to isolate and identify this organism from most patients with chancroid.