Recent Publications by CFE Educators

Aromatic amines have been studied for more than a half-century as model carcinogens representing a class of chemicals that form bulky adducts to the C8 position of guanine in DNA. Among these guanine adducts, the N-(2'-deoxyguanosin-8-yl)-aminofluorene (G-AF) and N-2-(2'-deoxyguanosin-8-yl)-acetylaminofluorene (G-AAF) derivatives are the best studied. Although G-AF and G-AAF differ by only an acetyl group, they exert different effects on DNA replication by replicative and high-fidelity DNA polymerases. Translesion synthesis of G-AF is achieved with high-fidelity polymerases, whereas replication of G-AAF requires specialized bypass polymerases. Here we have presented structures of G-AF as it undergoes one round of accurate replication by a high-fidelity DNA polymerase. Nucleotide incorporation opposite G-AF is achieved in solution and in the crystal, revealing how the polymerase accommodates and replicates past G-AF, but not G-AAF. Like an unmodified guanine, G-AF adopts a conformation that allows it to form Watson-Crick hydrogen bonds with an opposing cytosine that results in protrusion of the bulky fluorene moiety into the major groove. Although incorporation opposite G-AF is observed, the C:G-AF base pair induces distortions to the polymerase active site that slow translesion synthesis.

OBJECTIVE

The Accreditation Council for Graduate Medical Education (ACGME) has challenged program directors to assess their residents' core competencies, including communication and interpersonal skills (CIS). We report our institution's experience using a series of standardized patient encounters in an objective structured clinical examination (OSCE) to evaluate CIS in surgical residents.

METHODS

Standardized patients rated the residents' ability to maintain a patient-centered approach across 6 challenging communication tasks. Residents received verbal feedback from the patients after each encounter and completed a survey indicating their experience and comfort with each task. Individual and group reports documented resident competency and provided aggregate information for curriculum review. Formal grades were not assigned.

RESULTS

Twenty-two residents in 2 surgical residency programs piloted the assessment. The Generalizability of the assessment was 0.81. Scores of second- and third-year residents were not significantly different. Residents found the program to be helpful and able to assess their skills.

CONCLUSIONS

The standardized patient-based OSCE is an effective method to assess communication and interpersonal skills and provides useful information for curriculum review.

BACKGROUND

Information prescriptions (IPs) are prescriptions of specific, evidence-based information to manage health problems.

OBJECTIVE

To determine whether a pediatrician-provided IP would change parents' attitudes/behaviors about using Internet health information resources.

DESIGN, SETTING, AND PARTICIPANTS

We conducted a randomized controlled trial of parents visiting an academic general pediatric practice. Both groups received a preintervention paper survey and a telephone survey 2 to 3 weeks after their clinic visit. The intervention group was offered computer training and received the IP and training summary handout.

RESULTS

Final groups included 100 control and 97 intervention subjects. Of all parents, 68.0% had used the Internet in the past 6 months for health information and 52.8% used it for children's health information. The intervention group used the Internet more for general health information (P =.05) and child health information (P.001) than the control group. At follow-up, 51 (66.2%) of 77 Internet information resources used by the intervention group were prescribed by the pediatricians. Parents who used the IP (31 [32%] of 97 intervention parents) used the Internet for general health information (P.001) and child health information (P =.001) more than nonusers. Compared with nonusers, IP users were more likely to state they would use the IP again in the future (P =.02) and had already recommended the IP to family or friends more than nonusers (P =.001).

CONCLUSIONS

Parents of children in pediatric practices commonly use the Internet for general and children's health information. In this study, IPs were associated with specific parental attitude and behavior changes resulting in increased Internet utilization for general and child health information and for specific high-quality information resources. Pediatricians can implement IPs in their office.

Aerobic respiration generates reactive oxygen species that can damage guanine residues and lead to the production of 8-oxoguanine (8oxoG), the major mutagenic oxidative lesion in the genome. Oxidative damage is implicated in ageing and cancer, and its prevalence presents a constant challenge to DNA polymerases that ensure accurate transmission of genomic information. When these polymerases encounter 8oxoG, they frequently catalyse misincorporation of adenine in preference to accurate incorporation of cytosine. This results in the propagation of G to T transversions, which are commonly observed somatic mutations associated with human cancers. Here, we present sequential snapshots of a high-fidelity DNA polymerase during both accurate and mutagenic replication of 8oxoG. Comparison of these crystal structures reveals that 8oxoG induces an inversion of the mismatch recognition mechanisms that normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a cognate base pair whereas the 8oxoG.cytosine base pair behaves as a mismatch. These studies reveal a fundamental mechanism of error-prone replication and show how 8oxoG, and DNA lesions in general, can form mismatches that evade polymerase error-detection mechanisms, potentially leading to the stable incorporation of lethal mutations.

Accurate and safe diagnostic testing provides the crucial link between detection and optimal management of coronary artery disease (CAD). Noninvasive diagnostic testing for CAD may be less accurate in women than in men. Many noninvasive diagnostic modalities are available for this purpose. An exercise tolerance test provides an assessment of functional capacity and has the advantages of wide availability and low initial cost. However, exercise echocardiography may be the most cost-effective method for the initial assessment of coronary artery disease in intermediate-risk women owing to its higher sensitivity and specificity. Recent studies with electron-beam computed tomography reveal that women with no coronary calcification are very unlikely to have obstructive CAD. In symptomatic women with an intermediate likelihood of CAD, either an exercise treadmill test or exercise echocardiography is appropriate for initial screening and can provide useful prognostic information. Alternatively, an electron-beam computed tomographic scan with a 0 calcium score may spare many women with atypical chest pain or equivocal findings on an exercise tolerance test from undergoing more expensive stress imaging studies or coronary angiography. For high-risk symptomatic women, a more aggressive approach involving coronary angiography appears to be the preferred initial diagnostic strategy.

Despite its fundamental importance, the educational mission of most medical schools receives far less recognition and support than do the missions of research and patient care. This disparity is based, in part, on the predominance of discipline-based departments, which focus on the more sustainable enterprises of research and patient care. Where departmental teaching is emphasized, it tends to center on trainees directly associated with the department-leaving medical students unsupported. The authors argue that the ongoing erosion of the educational mission will never be reversed unless there are changes in the underlying structure of medical schools. Academies of medical educators are developing at a number of medical schools to advance the school-wide mission of education. The authors describe and compare key features of such organizations at eight medical schools, identified through an informal survey of the Society of Directors of Research in Medical Education, along with direct contacts with specific schools. Although these entities are relatively new, initial assessments suggest that they have already had a major impact on the recognition of teaching efforts by the faculty, fueled curricular reform, promoted educational scholarship, and garnered new resources to support teaching. The academy movement, as a structural approach to change, shows promise for reinvigorating the educational mission of academic medicine.

OBJECTIVES

To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved.

METHODS

Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years.

RESULTS

VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88).

CONCLUSIONS

STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.