Joseph C. Kolars

First-pass metabolism of cyclosporin by the gut.

Cyclosporin is thought to be exclusively metabolised in the liver. We instilled cyclosporin into the small bowel of 2 patients during the anhepatic phase of liver transplantation; cyclosporin metabolites were readily detected in portal venous blood. Our findings indicate that the small intestine is a major site of cyclosporin breakdown: such intestinal metabolism might help to explain the poor oral bioavailability and drug interactions of cyclosporin.

Medical schools in sub-Saharan Africa.

Small numbers of graduates from few medical schools, and emigration of graduates to other countries, contribute to low physician presence in sub-Saharan Africa. The Sub-Saharan African Medical School Study examined the challenges, innovations, and emerging trends in medical education in the region. We identified 168 medical schools; of the 146 surveyed, 105 (72%) responded. Findings from the study showed that countries are prioritising medical education scale-up as part of health-system strengthening, and we identified many innovations in premedical preparation, team-based education, and creative use of scarce research support. The study also drew attention to ubiquitous faculty shortages in basic and clinical sciences, weak physical infrastructure, and little use of external accreditation. Patterns recorded include the growth of private medical schools, community-based education, and international partnerships, and the benefit of research for faculty development. Ten recommendations provide guidance for efforts to strengthen medical education in sub-Saharan Africa.

Relationship between increased personal well-being and enhanced empathy among

BACKGROUND: While resident distress and its potential to negatively effect patient care have been well documented, little is known about resident well-being or its potential to enhance care.OBJECTIVE: We measured resident well-being and explored its relationship with empathy.DESIGN: Anonymous, cross-sectional survey.PARTICIPANTS: Internal medicine residents at Mayo Clinic Rochester (n=165, summer 2003).MEASUREMENTS: Well-being was measured using the previously validated Medical Outcomes Study 8-item Short Form (SF-8). Empathy was measured using the previously validated Perspective Taking (PT) and Empathetic Concerns (EC) Sub-scales of the Interpersonal Reactivity Index (IRI).RESULTS: Eighty-three (50%) residents responded to the survey. Mean scores for well-being as measured by the SF-8 were comparable to the general population, and empathy scores on the IRI were similar to other resident samples. Resident empathy on both the cognitive (PT) and emotive (EC) sub-scales of the IRI was higher for residents with higher mental well-being on the SF-8; however, this difference was statistically significant only for the cognitive sub-scale. The importance of a number of personal wellness promotion strategies differed for residents with higher mental well-being on the SF-8.CONCLUSIONS: High mental well-being was associated with enhanced resident empathy in this cross-sectional survey. Future studies need to explore the potential for high resident well-being to enhance medical care and competency in addition to exploring the negative consequences of resident distress. Studies investigating how to promote resident well-being are needed.

Comparison of urinary 6‐β‐cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity

The production of 14CO2 in the breath from an intravenous dose of [14C‐N‐methyl] ‐erythromycin (the erythromycin breath test [ERMBT]) and the measurement of the ratio of 6‐β‐cortisol to free cortisol (6‐β‐F/FF) in the urine have each been proposed as means of measuring hepatic P450IIIA catalytic activity in patients. We found that there was a significant correlation between the results of each test (r = 0.59, p < 0.001) in 47 patients who were without liver disease and who were not taking medications believed to influence P450IIIA catalytic activity. In the 24 of these patients who were subsequently treated with the P450IIIA substrate cyclosporine, the ERMBT result was highly correlated with the mean trough cyclosporine blood level observed; however, there was no correlation between urinary 6‐β‐F/FF and the cyclosporine blood levels. In a separate study of a patient during the anhepatic phase of liver transplantation surgery, the ERMBT result decreased by greater than 85%, whereas urinary 6‐β‐F/FF decreased by just 50%. We conclude that the ERMBT and urinary 6‐β‐F/FF do not always provide similar information about P450IIIA catalytic activity in patients, possibly because of extrahepatic production of 6‐β‐F. Of the two tests, the ERMBT appears to provide the most relevant information for cyclosporine administration.

Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA

A 40-year-old male liver allograft recipient had neurological dysfunction and renal failure while his cyclosporin blood levels were in the therapeutic range; these features recurred on rechallenge. The hypothesis that this toxic effect might have resulted from abnormal metabolism of cyclosporin by liver cytochrome P-450 IIIA was investigated with the [14C]erythromycin breath test, which is a measure of this enzymes activity. P-450 IIIA activity was decreased compared with that in controls, including other liver transplant recipients. Pretreatment with rifampicin, an inducer of P-450 IIIA, increased enzyme activity. After treatment with rifampicin the patient could be rechallenged with cyclosporin at a dose almost twice that which had previously been toxic. The patient died during a second transplantation and the microsomal content of P-450 IIIA was found to be low in the first transplant.

Effects of the 2011 Duty Hour Reforms on Interns and Their Patients: A Prospective Longitudinal Cohort Study

IMPORTANCE In 2003, the first phase of duty hour requirements for US residency programs recommended by the Accreditation Council for Graduate Medical Education (ACGME) was implemented. Evidence suggests that this first phase of duty hour requirements resulted in a modest improvement in resident well-being and patient safety. To build on these initial changes, the ACGME recommended a new set of duty hour requirements that took effect in July 2011. OBJECTIVE To determine the effects of the 2011 duty hour reforms on first-year residents (interns) and their patients. DESIGN As part of the Intern Health Study, we conducted a longitudinal cohort study comparing interns serving before (2009 and 2010) and interns serving after (2011) the implementation of the new duty hour requirements. SETTING Fifty-one residency programs at 14 university and community-based GME institutions. PARTICIPANTS A total of 2323 medical interns. MAIN OUTCOME MEASURES Self-reported duty hours, hours of sleep, depressive symptoms, well-being, and medical errors at 3, 6, 9, and 12 months of the internship year. RESULTS Fifty-eight percent of invited interns chose to participate in the study. Reported duty hours decreased from an average of 67.0 hours per week before the new rules to 64.3 hours per week after the new rules were instituted (P < .001). Despite the decrease in duty hours, there were no significant changes in hours slept (6.8 → 7.0; P = .17), depressive symptoms (5.8 → 5.7; P = .55) or well-being score (48.5 → 48.4; P = .86) reported by interns. With the new duty hour rules, the percentage of interns who reported concern about making a serious medical error increased from 19.9% to 23.3% (P = .007). CONCLUSIONS AND RELEVANCE Although interns report working fewer hours under the new duty hour restrictions, this decrease has not been accompanied by an increase in hours of sleep or an improvement in depressive symptoms or well-being but has been accompanied by an unanticipated increase in self-reported medical errors.

The erythromycin breath test as a predictor of cyclosporine blood levels

The daily dose of cyclosporine required to attain a desired blood level can vary greatly among patients. Because elimination of cyclosporine depends on its metabolism in the liver by an enzyme (cytochrome P‐450IIIA) that also demethylates erythromycin, we reasoned that the ability of patients to demethylate a test dose of erythromycin might be useful in estimating their appropriate daily doses of cyclosporine. Accordingly, the [14C‐N‐methyl] erythromycin breath test was administered to 32 patients before they received 3.0, 5.0, or 7.5 mg/kg/day cyclosporine to treat psoriasis. We found that a simple mathematical equation incorporating just the 14CO2 production, the age of the patient, and the daily dose of cyclosporine accounted for almost 80% (R2 = 0.78) of the interpatient variability in cyclosporine blood levels we observed. Our data indicate that P‐450IIIA activity largely accounts for the relationship between dose of cyclosporine and blood levels for an individual patient. We conclude that the erythromycin breath test may be a convenient guide for cyclosporine dosing.

The promise of competency-based education in the health professions for improving global health

Competency-based education (CBE) provides a useful alternative to time-based models for preparing health professionals and constructing educational programs. We describe the concept of ‘competence’ and ‘competencies’ as well as the critical curricular implications that derive from a focus on ‘competence’ rather than ‘time’. These implications include: defining educational outcomes, developing individualized learning pathways, setting standards, and the centrality of valid assessment so as to reflect stakeholder priorities. We also highlight four challenges to implementing CBE: identifying the health needs of the community, defining competencies, developing self-regulated and flexible learning options, and assessing learners for competence. While CBE has been a prominent focus of educational reform in resource-rich countries, we believe it has even more potential to align educational programs with health system priorities in more resource-limited settings. Because CBE begins with a careful consideration of the competencies desired in the health professional workforce to address health care priorities, it provides a vehicle for integrating the health needs of the country with the values of the profession.

Heterogeneity of Cytochrome P450IIIA Expression in Rat Gut Epithelia

The P450IIIA (CYP3A) cytochromes are a major family of enzymes that play an important role in the metabolism of many medications, including cyclosporine A, as well as some dietary xenobiotics, including aflatoxin B1. The purpose of the studies was to detect, localize, and characterize P450IIIA enzymes present throughout the digestive tract. To this end, P450IIIA-specific antibodies were used to examine gut epithelial microsomes and histological tissue sections obtained from the digestive tract of both male and female rats. P450IIIA-related proteins were detected in epithelia throughout the gut; however, the specific proteins expressed appeared to differ among digestive organs and between male and female rats. RNA obtained from the gut epithelia was also analyzed using P450IIIA-specific synthetic oligonucleotides as probes on Northern blots and as primers for the polymerase chain reaction. P450IIIA1, which is a dexamethasone inducible enzyme in liver, was also found to be induced by dexamethasone treatment in epithelia from stomach and jejunum, but not from colon or esophagus. It was concluded that P450IIIA enzymes are present in mature epithelia throughout the gastrointestinal tract. However, expression of the P450IIIA enzymes is influenced by anatomic location and gender.

Time Spent on Clinical Documentation: A Survey of Internal Medicine Residents and Program Directors

BACKGROUND Clinical documentation and clerical duties are substantial activities for internal medicine residents. Therefore, we sought to understand the perspectives of internal medicine residents regarding the time devoted to documentation and direct patient care, as well as the perceived frequency and importance of feedback on patient-related documentation. METHODS As part of the 2006 US Internal Medicine In-Training Examination, residents voluntarily completed a survey that included questions on the average daily hours spent in direct patient contact and clerical documentation during inpatient rotations. Residents and program directors were asked to report on the frequency and importance of feedback provided to trainees by faculty on patient-related documentation. RESULTS A total of 16 402 trainees (85.9%) and 235 PDs (61.7%) completed the survey. There were 67.9% of residents who reported spending in excess of 4 hours daily on documentation; only 38.9% reported spending this amount of time in direct patient contact. The majority of residents (56.5%) and program directors (63.0%) believed that feedback on documentation occurred less than 50% of the time. Program directors were more likely than residents to view feedback on documentation as highly important (73.2% vs 58.6%; P < .001). CONCLUSIONS Internal medicine residents perceive that they are spending excessive time in the hospital setting on clerical documentation. Further evaluation to understand specific inpatient activities of residents and the educational value of those activities is essential.