Recent Publications by CFE Educators

BACKGROUND

We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients.

METHODS

We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed.

RESULTS

A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline.

CONCLUSIONS

Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

INTRODUCTION

The prevalence of sexual problems among resident physicians has not been investigated.

AIM

To explore the sexual behavior of residents and fellows in training and to determine the incidence of sexual dysfunction in this population.

METHODS

Residents and fellows at our institution were invited to complete a demographic questionnaire, as well as two to three gender-specific validated instruments for the assessment of human sexuality.

MAIN OUTCOME MEASURES

The validated survey instruments selected were the International Index of Erectile Function (IIEF), the Index of Premature Ejaculation (IPE), and the Self-Esteem and Relationship Quality (SEAR) survey for male residents, and the Female Sexual Function Index (FSFI) and the Index of Sex Life (ISL) for female residents. Results were compared with established normative data and validated cut-off scores that were available. Pearson correlation coefficient was used to assess for relationships between variables.

RESULTS

There were 180 responses (83 female, 97 male, mean age 29 years), for a response rate of 20%. Among men, 90%, 67%, and 98% were in a relationship, married, and heterosexual, respectively. Among women, the same numbers were 80%, 55%, and 96%, respectively. Based on validated cut-off scores for the IIEF and FSFI, 13% of men reported ED (3% reported mild ED, 4% reported moderate ED, and 6% reported severe ED) and 60% of women were classified as "at high risk" for sexual problems, with desire disorders the most prevalent and orgasmic disorders the second most prevalent. There were significant gender differences with respect to the associations between sexual and relationship problems.

CONCLUSIONS

Sexual problems may be prevalent among residents in training, particularly female residents. Additional, larger studies that assess other quality of life measures and query sexual partners of residents are needed.

BACKGROUND

Differences in pathophysiology, diagnosis, and treatment of women with cardiovascular disease compared with men has become a major focus during the past decade. Nevertheless, little attention has focused on improving the quality of healthcare in women compared with other areas of cardiovascular medicine.

METHODS

To address this deficit, Duke University Medical Center convened a national Duke Clinical Research Institute (DCRI) Think Tank meeting, including basic science and clinical researchers, payers, legislators, clinical experts, government regulators, and members of the pharmaceutical and device industries. This report provides an overview of the discussions and proposed solutions.

RESULTS

Discussion concentrated on the development of strategies to improve the quality of health care for women with heart disease. Key components to improve quality care include: (1) enhance the quantity and quality of evidence-based medicine to guide care in women through improvements in trial design, enrollment and retention of women subjects, results analysis and reporting, and better incentives to perform research in women; (2) provide incentives to develop better data in women through mandating changes in the drug and device development and approval processes; (3) incorporate specific recommendations for women into guidelines when data are sufficient; and (4) apply proven sex-based differences in risk stratification, diagnostic testing, and drug usage and dosing in clinical care. Examples of possible strategies are included.

CONCLUSION

The above approach represents a necessary, but not sufficient, platform to improve the overall quality of healthcare in women with cardiovascular disease.

CONTEXT

Shortfalls in the US physician workforce are anticipated as the population ages and medical students' interest in careers in internal medicine (IM) has declined (particularly general IM, the primary specialty serving older adults). The factors influencing current students' career choices regarding IM are unclear.

OBJECTIVES

To describe medical students' career decision making regarding IM and to identify modifiable factors related to this decision making.

DESIGN, SETTING, AND PARTICIPANTS

Web-based cross-sectional survey of 1177 fourth-year medical students (82% response rate) at 11 US medical schools in spring 2007.

MAIN OUTCOME MEASURES

Demographics, debt, educational experiences, and number who chose or considered IM careers were measured. Factor analysis was performed to assess influences on career chosen. Logistic regression analysis was conducted to assess independent association of variables with IM career choice.

RESULTS

Of 1177 respondents, 274 (23.2%) planned careers in IM, including 24 (2.0%) in general IM. Only 228 (19.4%) responded that their core IM clerkship made a career in general IM seem more attractive, whereas 574 (48.8%) responded that it made a career in subspecialty IM more attractive. Three factors influenced career choice regarding IM: educational experiences in IM, the nature of patient care in IM, and lifestyle. Students were more likely to pursue careers in IM if they were male (odds ratio [OR] 1.75; 95% confidence interval [CI], 1.20-2.56), were attending a private school (OR, 1.88; 95% CI, 1.26-2.83), were favorably impressed with their educational experience in IM (OR, 4.57; 95% CI, 3.01-6.93), reported favorable feelings about caring for IM patients (OR, 8.72; 95% CI, 6.03-12.62), or reported a favorable impression of internists' lifestyle (OR, 2.00; 95% CI, 1.39-2.87).

CONCLUSIONS

Medical students valued the teaching during IM clerkships but expressed serious reservations about IM as a career. Students who reported more favorable impressions of the patients cared for by internists, the IM practice environment, and internists' lifestyle were more likely to pursue a career in IM.

OBJECTIVE

To report the occurrence of taurodontism in a clinical sample of Van der Woude syndrome (VWS) and describe its association with hypodontia and cleft type.

MATERIALS AND METHODS

This retrospective, cross-sectional study was carried out on chart reviews and radiographs of 13 persons with VWS. Mean age was 10 years 11 months +/- 1 year 5 months. Panoramic radiographs were used to confirm the presence or absence of teeth and to measure crown body and root lengths of mandibular first molars. Three-dimensional cone beam computed tomography (CT) scans were available on two persons with VWS. Both volumetric and linear measurements were obtained.

RESULTS

The occurrence of taurodontism of the mandibular first molar was 35%: 27% hypodont and 8% mesodont. Of the 13 subjects with VWS, 6 (4 males and 2 females) had at least one tooth identified with taurodontism. Half of the cases were unilateral and half were bilateral, and all of the unilateral cases were on the left side. Five of the six subjects with taurodontism had missing incisors and premolars. Taurodontism was two times more frequent in those who were missing their second premolars than in those who had their second premolars. There was no correlation between cleft type and presence of taurodontism. The cone beam CT pilot study on two persons showed very abnormal morphology of both crown and roots, which was not apparent on the standard panoramic radiograph. Both the volumetric and linear measurements of the ratio of crown body to root were highly indicative of taurodontism. Further genetic studies are needed.

CONCLUSION

There is a likely association between VWS and taurodontism.

OBJECTIVES/HYPOTHESIS

To determine the rate of salvage laryngectomy after failure of radiation or chemoradiation over 10-year course, identify factors associated with increased risk of treatment failure, assess survival after salvage laryngectomy.

STUDY DESIGN

Retrospective review.

METHODS

Twenty patients who underwent salvage total laryngectomy were studied. Overall interval to recurrence (ITR) was 9.9 months, overall postsalvage-laryngectomy survival (PSL-OAS) 25 months, and interval to death (PSL-ITD) 15.8 months. Mortality was 85%.

RESULTS

Four patients failed chemoradiation and 16 failed radiation alone. Based on treatment, there was no difference in ITR (12.8 vs. 8.8 months, P = .27) or PSL-OAS (27.5 vs. 24.4 months, P = .86). PSL-ITD was significantly higher after chemoradiation (27.5 vs. 12.2 months, P = .02). Advanced T-stage patients were significantly younger than early-stage (53 vs. 64 years, P = .02), but had no significant difference in ITR (12.7 vs. 6.8 months, P = .08), PSL-OAS (20.1 vs. 33.6 months, P = .35), or PSL-ITD (12 vs. 21.6 months, P = .1). Analysis by site and differentiation showed no significant differences. Heavy alcohol use/alcoholism was reported in >50%. Rate of fistulization was 20%. Three patients currently survive, with average postsalvage-laryngectomy disease-free survival (PSL-DFS) 77 months.

CONCLUSIONS

Salvage laryngectomy is an uncommon procedure (7% over 10-year period). There is no difference in survival after salvage laryngectomy for radiation or chemoradiation failure. Patients failing chemoradiation have longer PSL-ITD than those failing radiation alone. Patients with T3-4 tumors tend to be younger. T-stage of tumor does not affect rate of salvage procedure. Fistulae formed in 20%. Neither location nor differentiation affects survival. Surgical salvage after primary conservative treatment is associated with an approximately 2-year survival.

Recruitment of effector T cells to inflamed peripheral tissues is regulated by chemokines and their receptors, but the factors regulating recruitment to tumors remain largely undefined. Ionizing radiation (IR) therapy is a common treatment modality for breast and other cancers. Used as a cytocidal agent for proliferating cancer cells, IR in combination with immunotherapy has been shown to promote immune-mediated tumor destruction in preclinical studies. In this study we demonstrate that IR markedly enhanced the secretion by mouse and human breast cancer cells of CXCL16, a chemokine that binds to CXCR6 on Th1 and activated CD8 effector T cells, and plays an important role in their recruitment to sites of inflammation. Using a poorly immunogenic mouse model of breast cancer, we found that irradiation increased the migration of CD8(+)CXCR6(+) activated T cells to tumors in vitro and in vivo. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression following treatment with local IR to the tumor and Abs blocking the negative regulator of T cell activation, CTLA-4. These results provide the first evidence that IR can induce the secretion by cancer cells of proinflammatory chemotactic factors that recruit antitumor effector T cells. The ability of IR to convert tumors into "inflamed" peripheral tissues could be exploited to overcome obstacles at the effector phase of the antitumor immune response and improve the therapeutic efficacy of immunotherapy.

UNLABELLED

In this study, we developed a complete description of the morphology of the proximal femur. Then, using this framework, we (1) determined normal population means, standard deviations, and ranges; (2) established differences among subpopulations; and (3) showed correlations among the various measurements. To accomplish these objectives, we analyzed 375 adult femurs. Specimens were digitally photographed in standardized positions, measurements being obtained using ImageJ software. Three parameters of the head-neck relationship were assessed. Translation was examined through four raw offset measurements (anterior, posterior, superior, inferior) used to calculate anterior-posterior and superior-inferior ratios. Rotation was investigated through anteroposterior (AP) and lateral physeal angles. Concavity was examined using alpha, beta, gamma, and delta angles. Two parameters of the neck-shaft relationship were assessed, neck version and angle of inclination. Average anterior-posterior and superior-inferior ratios were 1.14 and 0.90. Average AP and lateral physeal angles were 74.33 degrees and 81.83 degrees , respectively. Averages for alpha, beta, gamma, and delta angles were 45.61 degrees , 41.85 degrees , 53.46 degrees , and 42.95 degrees , respectively. Average neck version and angle of inclination were 9.73 degrees and 129.23 degrees , respectively. Differences existed between males and females and between those younger and older than 50 years. Correlations were observed between translation and concavity, and translation and the neck-shaft relationships.

LEVEL OF EVIDENCE

Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Sumatriptan and the other triptan drugs target the serotonin receptor subtypes1B, 1D, and 1F (5-HT(1B/D/F)), and are prescribed widely in the treatment of migraine. An anti-migraine action of triptans has been postulated at multiple targets, within the brain and at both the central and peripheral terminals of trigeminal "pain-sensory" fibers. However, as triptan receptors are also located on "pain-sensory" afferents throughout the body, it is surprising that triptans only reduce migraine pain in humans, and experimental cranial pain in animals. Here we tested the hypothesis that sumatriptan can indeed reduce non-cranial, somatic and visceral pain in behavioral models in mice. Because sumatriptan must cross the blood brain barrier to reach somatic afferent terminals in the spinal cord, we compared systemic to direct spinal (intrathecal) sumatriptan. Acute nociceptive thresholds were not altered by sumatriptan pre-treatment, regardless of route. However, in behavioral models of persistent inflammatory pain, we found a profound anti-hyperalgesic action of intrathecal, but not systemic, sumatriptan. By contrast, sumatriptan was completely ineffective in an experimental model of neuropathic pain. The pronounced activity of intrathecal sumatriptan against inflammatory pain in mice raises the possibility that there is a wider spectrum of therapeutic indications for triptans beyond headache.