Demonstrating bioequivalence using clinical endpoint studies.

For drug products not amenable to blood level studies, clinical endpoint studies have been used as an indirect measure of formulation difference in bioavailability between test and reference products. However, clinical endpoint studies are not as sensitive in detecting formulation differences as blood level studies and offer numerous challenges to both regulatory authorities and sponsors. The objective of this article is not to suggest new regulatory policies, but to explore new methodologies and alternative solutions to clinical endpoint bioequivalence (BE) studies, which are used when a blood level study is not considered to be appropriate. To achieve this objective, this article identifies situations where a clinical endpoint study might be appropriate, lists the advantages and disadvantages of this type of study design, and discusses possible alternative solutions. It is concluded that future evidence-based research is needed to explore new methodologies such as clinical trial simulations of various study designs, new statistical methods, and new in vitro methods to demonstrate BE.

Marbofloxacin for the treatment of experimentally induced Mycoplasma haemofelis infection in cats.

BACKGROUND: Administration of tetracyclines or fluoroquinolones is associated with improvement in clinical and laboratory abnormalities in cats infected with Mycoplasma haemofelis. No treatment protocol has consistently eliminated the organism, and antimicrobial susceptibility may vary among M. haemofelis isolates. Continued search for effective therapies is warranted. HYPOTHESIS: Marbofloxacin administered at the onset of clinical illness will be safe and effective for the treatment of M. haemofelis. ANIMALS: Fourteen young adult, laboratory-reared cats housed together in a specific pathogen-free facility. METHODS: Twelve cats were inoculated IV with 2.0 mL of blood from 2 M. haemofelis positive cats. Clinical parameters were assessed daily. CBC and hemoplasma polymerase chain reaction (PCR) assay were performed before inoculation, weekly for 1-3 weeks postinoculation (PI) and twice weekly 3-6 weeks PI. Treatment with marbofloxacin (2.75 mg/kg PO daily for 14 days) was initiated in 6 randomly selected cats when PCV was <30% or fever was >102.5 degrees F (39.2 degrees C). Cats that were PCR positive on day 7 of therapy were treated for 28 days. Cats that were PCR negative on day 42 PI were treated with 20 mg/kg methylprednisolone acetate IM on day 50 PI. RESULTS: Significant differences between groups on some days after inoculation included higher PCV and red blood cell counts, lower mean cell volume, and higher mean cell hemoglobin content in marbofloxacin-treated cats. No differences in PCR assay results were noted between groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Marbofloxacin was safe and resulted in more rapid hematologic improvement in M. haemofelis-infected cats, but did not change clinical scores and did not consistently eliminate infection.

Occupational human immunodeficiency virus exposure among residents and medical students: an analysis of 5-year follow-up data.

BACKGROUND: Findings of a needlestick survey at our institution yielded an estimate that 1 case of occupationally acquired human immunodeficiency virus (HIV) among the approximately 1100 residents and third- and fourth-year medical students would potentially occur every 2 to 3 years, and also revealed types of exposures, circumstances, rates of reporting, and reasons for not reporting. OBJECTIVE: The present study is a 5-year follow-up study to investigate changes in these parameters. METHODS: A self-administered, anonymous 2-page questionnaire covering occupational exposures and other risk factors was distributed to medical students in classes, and to residents in grand rounds and required conferences. The response rate was 71%. RESULTS: The incidence of needlestick accidents dropped dramatically over 5 years (1994-1995 vs 1989-1990), especially for surgical residents. Because the proportion of known sources positive for HIV increased over the same period, estimates of occupational HIV risk remain essentially the same, with a projection that 1 student or resident would be expected to experience an occupationally acquired HIV infection approximately every 2 years. The nonoccupational risk for this population, in contrast, seems to be lower than in their age group as a whole. CONCLUSIONS: While the decrease in overall occupational exposures (especially for surgical residents) coupled with slight increases in rates of exposure documentation and use of universal precautions constitute positive findings, the increased proportion of exposure sources who are HIV positive leads to an unchanged estimate of occupational HIV risk for residents and students. Study findings therefore support the continued need for educational efforts aimed at prevention, along with timely dissemination of advances in approaches to postexposure prophylaxis.

Risk of needlesticks and occupational exposures among residents and medical students.

PROBLEM: Occupational exposure to human immunodeficiency virus (HIV) disease is a problem of concern to all health care workers, especially those in large urban teaching hospitals with large numbers of HIV-positive patients. METHOD: The self-reported incidence of needlesticks and other exposures to patients' blood and body fluids in 550 medical students and residents at the Los Angeles County-University of Southern California Medical Center during the 1989 through 1990 training year was studied by means of an anonymous survey. RESULTS: Seventy-one percent of respondents reported one or more needlesticks or other exposures during the training year. Surgical residents had a sixfold greater rate of occupational exposure compared with medicine residents and were significantly more likely to experience suture needlesticks, cuts, open wound contamination, and mucous membrane exposure. Medical students generally were at somewhat lower risk compared with residents, but had greater rates of hollow-needle puncture accidents. No trend was found for accidental exposure by level of residency training. The known HIV-positive exposure rate for students and residents was 9.5% per person per year. Only 9% of exposures were actually reported to the health center. CONCLUSIONS: Based on the rate of exposures reported, numbers of known and estimated HIV-positive patients, and previously published HIV seroconversion rates, we would expect an annual rate of HIV seroconversion rates, we would expect an annual rate of HIV seroconversion as a result of occupational exposures of between 27 and 46 per 100,000. This rate is similar to the leading cause of death in this age group--motor vehicle accidents--and is equivalent to one student or resident in this medical center seroconverting every 2 to 3 years. Although only a portion of accidental exposures are regarded as preventable, these data emphasize the importance of increased efforts toward improved education, prevention, and accessibility of protective equipment.

Relaxin increases insulin-like growth factors (IGFs) and IGF-binding proteins of the pig uterus in vivo.

Relaxin promotes growth of reproductive tissues, including the uterus. Although we have evidence of a role for insulin-like growth factor I (IGF-I) in mediating relaxin-induced growth of porcine granulosa cells in vitro, the mechanism of action by which relaxin enhances uterine growth has not been identified. To investigate a role for the uterine insulin-like growth factor (IGF) system in relaxin-induced uterine growth, we monitored the effects of relaxin on porcine IGFs and IGF-binding proteins (IGFBPs) in vivo. The trophic effects of relaxin on the uterus were elicited by administering relaxin or saline to prepubertal gilts every 6 h for 54 h. Three hours after the last injection, uterine flushes, uteri, follicular fluid, and ovaries were collected. Estradiol was measured in plasma and follicular fluid to confirm the prepubertal status of each animal. Significantly higher concentrations of uterine lumen IGF-I (P < 0.05) and IGF-II (P < 0.01) were observed in animals treated with relaxin. However, relaxin administration did not affect uterine IGF-I and -II gene expression, as determined by a ribonuclease protection assay and Northern analysis, respectively. In uterine flushes, relaxin treatment increased an IGFBP doublet (33 and 34.5 kDa) and IGFBP-3. The uterine IGFBP doublet was identified as IGFBP-2 by immunoprecipitation. Plasma or follicular fluid IGFs and IGFBPs were unaffected by relaxin administration. In addition, relaxin did not influence IGF-I binding to its uterine receptor. This is the first study to demonstrate regulation of the pig uterine IGF system by relaxin. In conclusion, the data point to IGF-I, IGF-II, IGFBP-2, and IGFBP-3 as putative mediators of relaxin-induced uterine growth in the pig.

Who provides health care to children and adolescents in the United States?

Face-to-face visits by children and adolescents in office-based practice in the mid-1970s were studied. Pediatricians, family physicians, and general practitioners accounted for 35%, 6%, and 30%, respectively, of all child visits. Although 40% to 45% of preventive and medical encounters were with pediatricians, only 12% of visits for minor surgery, 20% of visits for psychosocial problems, and 9% of visits for combined medical-surgical reasons were to pediatricians. Only in very young children did pediatricians provide a substantial proportion of care for each of the types of visits. For some common diagnoses (acne, refractive error) most care was provided by specialists other than primary care specialists, but less than 16% of all preventive care visits (including routine eye examinations) was provided by specialists other than primary care physicians. A substantial proportion of the prenatal care and management of minor trauma was provided by family physicians and general practitioners. Although the limitations of the study (including an average response rate of 55%, exclusion of certain specialties and institutional physicians, sampling at different times of the year, lack of control for area of location of practice, and lack of information about response rates of different types of physicians within each specialty) preclude definitive conclusions, the findings raise important questions for future study.

Effect of on-site facilities on use of diagnostic radiology by non-radiologists.

This study uses self-reports from a nationwide sample of 5447 physicians in ten medical and surgical specialties to assess the impact of on-site facilities on the use of radiologic examinations by non-radiologists. Data from 169,559 patient visits show that when on-site radiologic facilities are available to non-radiologists, radiographs increase by a factor of 1.2 (internal medicine) to 1.7 (pediatrics). Use of radiologic examinations is up to four times greater for hospitalized compared with nonhospitalized patients and is slightly higher for hospital-based physicians and for younger physicians.

Do physicians spend less time with older patients?

In view of the additional time that older persons require for giving and receiving information, as well as for the examination process, it is important for manpower and reimbursement planning to better understand the nature of the physician-patient encounter with the elderly. We examined a series of national surveys of physicians' professional activities and found that physicians tend to spend less time with their older patients and also that encounter time by physicians in different specialties varies widely. Internists and cardiologists spend substantially more time with patients compared with general and family practitioners. For 65-74-year-old ambulatory patients, the average visit lengths are 18.3 minutes for internists, 18.0 for cardiologists, 11.2 for general practitioners, and 12.1 for family practitioners. Compared with ambulatory visit lengths for patients aged 45 to 64 years, average encounter times for 75-year-olds with family physicians were 0.8 minutes shorter, with general practitioners 1.2 minutes shorter, with internists 2.3 minutes shorter, and with cardiologists 3.0 minutes shorter. However, when all characteristics of the visit were considered, the effect of patient age remained significant only for general practitioners. A multivariate analysis of factors related to physician time for ambulatory care showed that more time is associated with multiple problems, problem severity, and the use of diagnostic testing. For general and family practice, the greater the number of previous visits for a problem, the shorter the encounter time is. Additional characteristics associated with shorter physician-patient encounter times include the volume of patients per week and the use of physician assistants within the practice. These findings have implications for medical education and manpower projections.

Are physicians sensitive to the special problems of older patients?

The sensitivity of primary care physicians to the health care needs of older patients was explored by means of an analysis of the use of diagnostic tests and therapeutic procedures during ambulatory visits. Survey data on a total of 28,265 visits to internists, family and general practitioners were examined to determine possible age-related differences in care. The study found that diagnostic testing falls off significantly for patients 75 years of age or older and that internists use substantially more tests for each age group than do family and general practitioners. The pattern of use of diagnostic tests in this secondary analysis does not address the issue of "appropriateness" but does suggest a pattern that makes little sense based on the known distribution of disease and functional disability in aging populations.

Neurosurgery in the United States: a log-diary study.

The Division of Research in Medical Education and of the University of Southern California, with the cooperation and assistance of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons, has conducted a national study of the professional activities of neurological surgeons in the United States. One of a series of 24 surveys of medical and surgical specialties, the survey obtained information on patient workloads, the allocation of physician time, the characteristics of patients and the circumstances under which they were seen, patient diagnoses, and the care that was provided--including whether an operation was performed. This paper provides a selection of the findings deemed most relevant to manpower issues in neurosurgery. A later paper will examine regional differences in patient care, including the frequency with which selected surgical procedures are used for different clinical conditions.

Initial experience with a multi-station objective structured teaching skills evaluation.

PURPOSE: To explore the applicability of using an objective structured evaluation to assess community preceptors' teaching performances. METHOD: The authors developed and, in 1996, administered an objective structured teaching evaluation (OSTE) at the University of California, Irvine, College of Medicine. They compared assessments of teaching skills made by faculty observers and standardized students, and examined instrument reliability, realism, and utility. RESULTS: Reliabilities of the OSTE varied with individual stations but, in several instances, approached acceptable standards. Faculty observers' and standardized students' evaluations of preceptors' performances were similar. Participants' feedback indicated that the greatest OSTE-related benefit was derived by the faculty observers. CONCLUSIONS: An OSTE that reflects realistic teaching situations can be successfully developed. Objective structured evaluation can be successfully applied to assessing faculty teaching performance. However, it may be no more discriminating than are student evaluations. An OSTE's utility may be greatest in guiding faculty development initiatives.

Assessing the acquisition of core clinical skills through the use of serial standardized patient assessments.

PURPOSE: Students in many medical schools now undergo multiple standardized-patient-based assessments. In this study, the authors examine the ability of such serial assessments to detect interval learning. METHOD: Twenty-one students from the University of California, Irvine, College of Medicine, class of 1999, underwent a clinical skills appraisal after three months of their third-year instruction. After nine months, all 89 members of that class completed an OSCE. Subsequently, all 87 students in the class of 2000 also completed clinical skills assessments after their third and ninth months of third-year instruction. All of these exercises included identical or similar stations measuring history, physical examination, and communication skills. Communication skills were measured somewhat differently during some of the exercises, using checklists that were either "content-" or "process-"oriented. The authors compared the performances for all groups. RESULTS: Both classes demonstrated significant improvement in physical examination performance, while their history performances remained unchanged. According to the assessments, their communication skills deteriorated over the course of their third-year instruction. Repeated exposures to similar or identical cases on the serial assessments did not impact the students' performances. Both content- and process-oriented measures of communication skills yielded highly similar results. CONCLUSIONS: Serial assessments using standardized patients can detect interval changes in performance that are independent of repeated exposures to similar or identical cases. Changes detected using this approach may have important curricular implications.

Neurosurgical manpower: the physician's viewpoint.

This paper reports a national study of physicians in 24 medical and surgical specialties, and reveals the opinions of neurosurgeons and their professional colleagues with regard to the adequacy of the supply of neurosurgical manpower. Among neurosurgeons, 30.4% believe the supply to be excessive, 60.1% think it is about right, 7.5% believe that there is a shortage, and 2.0% have no opinion. Neurologists' opinions do not differ significantly from those of neurosurgeons, but physicians and surgeons in 22 other specialties are significantly less likely to regard the supply as excessive and are more likely to perceive a shortage. Primary care physicians, as a group, are most likely to perceive a shortage, and least likely to indicate an excess. Among the 24 specialties studied, 9.3% of physicians believe the supply of neurosurgeons to be excessive, 55.1% think it is about right, 22.9% believe that there is a shortage, and 12.8% have no opinion.

Patient counseling by specialists in internal medicine: results of a nationwide survey.

An analysis of patient care data from a national sample of physicians in ten subspecialties of internal medicine was undertaken to determine rates of patient counseling in specialized medical care. The analysis, which was based on 91,226 patient encounters in both ambulatory and hospital settings, revealed that medical specialists employ patient education counseling in 12.3% of encounters, family/social/sexual counseling in 2.7%, and therapeutic listening/reassurance in 14.0%--rates that are 2 to 3 times those for primary care physicians. Among subspecialties, cardiologists have the highest rates of patient education and family/social/sexual counseling, and the second highest rates of therapeutic listening. (Rheumatology is highest in the latter category). Rates of patient education and therapeutic listening are higher for office-based physicians and for ambulatory care (especially ambulatory care provided by board-certified physicians). Patient education is more frequent for ambulatory first visits and consultations, whereas therapeutic listening is more frequent for 'principal care' patients seen in either ambulatory settings or in the hospital. Highest rates of family/social/sexual counseling occur for ambulatory first visits with nephrologists and ambulatory consultations with cardiologists.

Patient counselling by primary care physicians: results of a nationwide survey.

The rate of patient counseling in primary care medicine is a pivotal element of inter-specialty differences in styles of care. Using national data on patient care provided in both ambulatory care settings and in the hospital, this study examines the use of counseling by general and family practitioners, pediatricians, internists, and obstetrician/gynecologists. The findings show substantial differences based on physician specialty, with highest rates of counseling for family practitioners and internists, and rates of patient education for these two specialties almost three times that for general practitioners. The data also show generally higher counseling rates for hospital care and for first encounters with patients, and a tendency for office-based pediatricians and solo general practitioners to use less patient counseling compared to their institution-based counterparts. Projections of annual visit rates for the United States show that general practice and internal medicine account for a disproportionate amount of patient counseling compared to other primary care specialties, based on patient volume.

A racial and ethnic comparison of family formation and contraceptive practices among low-income women.

Low-income women's histories of pregnancies, their use or nonuse of contraception, and their marital status showed racial and ethnic differences in family formation patterns and fertility control practices. Data were analyzed from a survey of 918 low-income women in Los Angeles County. The sample contained about equal numbers of non-Hispanic whites, blacks, and Hispanics. The use of stratified samples equalized the poverty-level composition of the three racial and ethnic groups. First pregnancies for white and black women resulted primarily from nonuse of contraception while unmarried, but almost half of first pregnancies among Hispanics were intentional. Marital dissolution following pregnancy or childbearing was common among low-income whites and blacks, but Hispanics were more likely to have an intact marriage along with a higher average parity. Analyses of histories of pregnancies while controlling for demographic characteristics showed that racial and ethnic differences in rates of different types of pregnancies (classified as intended, accidental, or unprotected) and rates of abortion did not remain significant after adjustment for respondent characteristics and years of exposure to possible pregnancy. Actual parity, however, remained significant when these factors were controlled. Thus, results document distinctive patterns of family formation for low-income women in racial and ethnic subgroups of this population. Implications of these patterns of family formation for economic well-being are discussed.

Hypoglycemia, enteritis, and spiking mortality in Georgia broiler chickens: experimental reproduction in broiler breeder chicks.

The clinical signs, hypoglycemia, and mortality of "spiking mortality syndrome" were experimentally reproduced. Seven groups of day-old male primary broiler breeder chicks were orally inoculated with tissue and/or fecal-urate homogenates taken from field broilers with spiking mortality syndrome and from field broilers with enteritis and/or runting-stunting syndrome. All homogenates used as inocula were shown by transmission electron microscopy and negative staining to contain arenavirus-like particles. Inocula produced from field broilers with spiking mortality syndrome contained the highest numbers of the arena-virus-like particles and produced the highest percentage of hypoglycemic chicks 13-15 days postinoculation after a 5-to-9-hour fast. These homogenates also produced the most significant differences in mean plasma growth hormone and insulin-like growth factor-1 levels. The significance of the arenavirus-like particles is unknown but is currently being investigated.

Willingness to treat HIV-positive patients at different stages of medical education and experience.

The willingness of physicians to provide care to HIV-positive patients has been linked to a number of attitudinal factors, but little is known concerning the impact of premedical, medical, and residency training on these factors. The purpose of this study is to elicit responses to the same series of questions concerning HIV and its treatment from respondents at different stages of training, to detect trends in attitudes and to measure the impact of those attitudes on willingness to provide care for HIV/AIDS patients. Study data come from a cross-sectional survey (n = 249) of respondents across the training continuum, from premedical students to faculty physicians, using a self-administered questionnaire at a single medical school. The response rate was 59.6%. The study showed significant decreases in personal fear and misgivings concerning HIV, coupled with a substantial decrease in the perceived need for testing of non-high-risk individuals, as respondents gained additional education and training. Overall, the intent to treat HIV did not change significantly by training level, but multivariate analyses showed that while the initially strong influence of attitudes toward AIDS and its attendant risks diminishes, comfort relative to being around homosexuals per se continues to exert an impact on the intent to treat. Appropriate use of protective measures when providing care becomes far more common once individuals enter their clinical training years. The impact of medical education through its entire continuum therefore shows a positive impact on attitudes toward HIV, despite the absence of a significant trend in respondents' stated intent to treat. However, negative attitudes toward homosexuals continue to exert a negative influence on intent to treat that endures into the clinical training years.

Alcohol and drug abuse in an urban trauma center: predictors of screening and detection.

Studies of the prevalence of alcohol and drug abuse among trauma patients have produced recommendations that all trauma patients be screened for these substances. But a national survey of trauma centers showed that just 72.0% of level 1 trauma centers routinely obtain blood alcohol levels on trauma patients and only 50.4% routinely utilize toxicology screens. Utilizing patient summary data collected on 2,246 trauma patients treated in the Emergency Department of Long Beach (CA) Memorial Medical Center over a 2.5 year period, and laboratory results for a random sample of 246 of these patients, this study sought to determine patient and presenting problem characteristics associated with screening and positive test results in centers (such as ours) where screening is done selectively. Results show that 75.4% of trauma patients are screened for blood alcohol levels, and 58.5% are given a urine toxicology, with lowest rates for 12-20 year olds and highest rates for patients over 40 who were confused or incomprehensible. Men were slightly more likely to be screened for blood alcohol than women, but their positivity rate was 2.5 times higher; by contrast, the toxicology positivity rate did not differ significantly by gender. A positive finding for either test was associated with a 40% higher rate of positivity for the other.

Health promotion for elderly patients.

A review of the literature on health promotion for the elderly reveals that changes in behavior, recognized as beneficial if made early in life, also increase longevity and quality of life if made in one's later years. National survey data show that although people over 65 years are less likely to have harmful health and nutritional habits than are middle-aged adults, they are also less aware of the effect of behavioral patterns on health. Physician- and patient-provided data indicating that education and screening exams are provided less frequently to the elderly suggest possible age-related deficits in health promotion and preventive care. Expansion of physicians' efforts aimed at health promotion for the elderly could reduce morbidity and improve quality of life for this growing population by delaying the onset of dependency.