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1.  Testosterone and Abnormal Glucose Metabolism in an Inner-City Cohort 
Journal of men's health  2012;9(3):10.1016/j.jomh.2012.03.010.
Background
Low testosterone (T) has been associated with insulin resistance and diabetes mellitus (DM) among men in population-based studies. These studies included racially diverse men, but did not target for inclusion individuals with opiate use, Hepatitis C Virus (HCV) infection, or Human Immunodeficiency Virus (HIV) infection, which disproportionately affect inner-city populations and may alter the relationship between T and DM.
Methods
We studied the association between free T (FT) and abnormal glucose metabolism among male participants in the Study of HIV, Injection Drug Use, Nutrition, and Endocrinology (SHINE). We used logistic regression to examine the relationship between log FT and both insulin resistance and prediabetes/DM.
Results
Of 175 men, 43 (24.6%) had low FT (FT < 52 pg/mL). There were more men in the low FT group on methadone maintenance (39.5% v. 15.2%, p=.001), but there was no difference in FT by HIV or HCV status. Overall, 23 men (13.1%) had prediabetes/DM, which was unrelated to FT (OR of prediabetes/DM for each log increase in FT = 0.56, 95% CI 0.13–2.41). FT was also not related to insulin resistance.
Conclusions
The prevalence of hypogonadism was high in this inner-city cohort and was associated with methadone use. However, low FT was not related to insulin resistance or prediabetes/DM. Continued work to identify diabetes risk factors among inner-city populations will help determine targets for intervention to reduce diabetes incidence. Treatment trials of testosterone to reduce diabetes among hypogonadal men may be of particular relevance to opiate users, many of whom are hypogonadal.
doi:10.1016/j.jomh.2012.03.010
PMCID: PMC3809764  PMID: 24174995
Testosterone; Diabetes; Insulin Resistance; Methadone
2.  Factors Affecting Clinician Educator Encouragement of Routine HIV Testing Among Trainees 
BACKGROUND
Adoption of CDC recommendations for routine, voluntary HIV screening of all Americans age 13–64 years has been slow. One method to increase adherence to clinical practice guidelines is through medical school and residency training.
OBJECTIVE
To explore the attitudes, barriers, and behaviors of clinician educators (CEs) regarding advocating routine HIV testing to their trainees.
DESIGN/PARTICIPANTS
We analyzed CE responses to a 2009 survey of Society of General Internal Medicine members from community, VA, and university-affiliated clinics regarding HIV testing practices.
MAIN MEASURES
Clinician educators were asked about their outpatient practices, knowledge and attitudes regarding the revised CDC recommendations and whether they encouraged trainees to perform routine HIV testing. Associations between HIV testing knowledge and attitudes and encouraging trainees to perform routine HIV testing were estimated using bivariate and multivariable logistic regression.
RESULTS
Of 515 respondents, 367 (71.3%) indicated they supervised trainees in an outpatient general internal medicine clinic. These CEs demonstrated suboptimal knowledge of CDC guidelines and over a third reported continued risk-based testing. Among CEs, 196 (53.4%) reported that they encourage trainees to perform routine HIV testing. Higher knowledge scores (aOR 5.10 (2.16, 12.0)) and more positive attitudes toward testing (aOR 8.83 (4.21, 18.5)) were independently associated with encouraging trainees to screen for HIV. Reasons for not encouraging trainees to screen included perceived low local prevalence (37.2%), competing teaching priorities (34.6%), and a busy clinic environment (34.0%).
CONCLUSIONS
Clinician educators have a special role in the dissemination of the CDC recommendations as they impact the knowledge and attitudes of newly practicing physicians. Despite awareness of CDC recommendations, many CEs do not recommend universal HIV testing to trainees. Interventions that improve faculty knowledge of HIV testing recommendations and address barriers in resident clinics may enhance adoption of routine HIV testing.
doi:10.1007/s11606-012-1985-9
PMCID: PMC3378731  PMID: 22302354
HIV; screening; clinician educator; residency training
4.  Provider and Practice Characteristics Associated with Use of Rapid HIV Testing by General Internists 
Journal of General Internal Medicine  2011;26(11):1258-1264.
BACKGROUND
Rapid HIV testing could increase routine HIV testing. Most previous studies of rapid testing were conducted in acute care settings, and few described the primary care providers’ perspective.
OBJECTIVE
To identify characteristics of general internal medicine physicians with access to rapid HIV testing, and to determine whether such access is associated with differences in HIV-testing practices or perceived HIV-testing barriers.
DESIGN
Web-based cross-sectional survey conducted in 2009.
PARTICIPANTS
A total of 406 physician members of the Society of General Internal Medicine who supervise residents or provide care in outpatient settings.
MAIN MEASURES
Surveys assessed provider and practice characteristics, HIV-testing types, HIV-testing behavior, and potential barriers to HIV testing.
RESULTS
Among respondents, 15% had access to rapid HIV testing. In multivariable analysis, physicians were more likely to report access to rapid testing if they were non-white (OR 0.45, 95% CI 0.22, 0.91), had more years since completing training (OR 1.06, 95% CI 1.02, 1.10), practiced in the northeastern US (OR 2.35; 95% CI 1.28, 4.32), or their practice included a higher percentage of uninsured patients (OR 1.03; 95% CI 1.01, 1.04). Internists with access to rapid testing reported fewer barriers to HIV testing. More respondents with rapid than standard testing reported at least 25% of their patients received HIV testing (51% versus 35%, p = 0.02). However, access to rapid HIV testing was not significantly associated with the estimated proportion of patients receiving HIV testing within the previous 30 days (7.24% vs. 4.58%, p = 0.06).
CONCLUSION
Relatively few internists have access to rapid HIV testing in outpatient settings, with greater availability of rapid testing in community-based clinics and in the northeastern US. Future research may determine whether access to rapid testing in primary care settings will impact routinizing HIV testing.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-011-1764-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-011-1764-z
PMCID: PMC3208478  PMID: 21710314
HIV testing; rapid HIV testing; HIV/AIDS; general internal medicine physicians; HIV prevention; medical practice setting
5.  Update in HIV Medicine for the Generalist 
doi:10.1007/s11606-010-1580-x
PMCID: PMC3077485  PMID: 21140297
HIV/AIDS; prevention; screening
7.  Prevalence of Low Bone Mineral Density in a Low-Income Inner-City Population 
Bone mineral density (BMD) is an important factor linked to bone health. Little is known of the prevalence of low BMD and its associated risk factors in an urban underserved population. Between 2001 and 2004, we recruited 338 subjects who completed drug use and medical history questionnaires, underwent hormonal measurements, and underwent whole-body dual-energy X-ray absorptiometry (DXA) for evaluation of BMD and body composition. Of these, 132 subjects had site-specific DXA (lumbar spine and hip) performed. Osteoporosis was defined as a T-score of –2.5 or less for men 50 years of age and older and postmenopausal women and a Z-score of –2.0 or less in men younger than 50 years of age and premenopausal women at either the lumbar spine, total hip, or femoral neck, according to National Osteoporosis Foundation (NOF) guidelines. The cohort consisted of mostly African-American, middle-aged people with a high prevalence of illicit drug use, 50% HIV+, and 39% hepatitis C+. Osteoporosis was identified in 22% of subjects (24 men, 5 women), with the majority of cases (90%) attributable to osteoporosis at the lumbar spine. Osteoporosis was more common in men than in women. Lower whole-body BMD among women was associated with multiple risk factors, but only with lower lean mass among men. Osteoporosis was highly prevalent in men, mainly at the spine. The risk factors for bone loss in this population need to be further clarified. Screening men for osteoporosis starting at age 50 might be warranted in this population given the multiple risk factors and the unexpectedly high prevalence of low BMD. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.221
PMCID: PMC3179342  PMID: 20721937
OSTEOPOROSIS; BONE MINERAL DENSITY; HIV; BMI; INNER CITY
8.  General Internists' Beliefs, Behaviors, and Perceived Barriers to Routine HIV Screening in Primary Care 
The Centers for Disease Control and Prevention (CDC) recommends routine HIV screening in primary care but little is known about general internists' views of this practice. We conducted a national, cross-sectional, Internet-based survey of 446 general internists in 2009 regarding their HIV screening behaviors, beliefs, and perceived barriers to routine HIV screening in outpatient internal medicine practices. Internists' awareness of revised CDC guidelines was high (88%), but only 52% had increased HIV testing, 61% offered HIV screening regardless of risk, and a median 2% (range 0-67%) of their patients were tested in the past month. Internists practicing in perceived higher risk communities reported greater HIV screening. Consent requirements were a barrier to screening, particularly for VA providers and those practicing in states with HIV consent statutes inconsistent with CDC guidelines. Interventions that promote HIV screening regardless of risk and streamlined consent requirements will likely increase adoption of routine HIV screening in general medicine practices.
doi:10.1521/aeap.2011.23.3_supp.70
PMCID: PMC3196638  PMID: 21689038
9.  Illicit drug use and HIV treatment outcomes in a US cohort 
AIDS (London, England)  2008;22(3):357-365.
Objective
To determine the prevalence of illicit drug use and the impact on HIV treatment.
Design
Multivariable regression of cross-sectional data from 1163 HIV-infected and 294 controls from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
Methods
An analysis of (1) prevalence of specific illicit drug use (ever, current), (2) being on HAART among those with an indication and (3) current HIV RNA and CD4 cell count among HAART users.
Results
Median age was 42 years, approximately 50% were non-Caucasian and 33% were women. Eighty-six percent of HIV-infected and 67% of controls reported ever using illicit drugs (P <0.0001); 28% of HIV-infected and 16% of controls reported current use (P = 0.0001). In adjusted models, current cocaine use and past heroin use were associated with not currently being on HAART. Among HAART users, those reporting past heroin use were as likely to have an undetectable HIV viral load as those who had never used heroin. Current and past cocaine use and current heroin use was associated with lower odds of undetectable HIV RNA. Past amphetamine use was associated with having an undetectable HIV. Similar results were seen for CD4 lymphocyte counts.
Conclusion
Illicit drug use in the US is common, although far fewer report current use than past use. Among HIV-infected patients, understanding of the type of illicit drugs used and whether drug use was in the past or ongoing is important, because of their differential effects on HIV treatment outcomes.
doi:10.1097/QAD.0b013e3282f3cc21
PMCID: PMC3189479  PMID: 18195562
amphetamines; cocaine; heroin; HIV; street drugs; viral load
10.  A Multicenter Study of Internal Medicine Residents' Perceptions of Training, Competence, and Performance in Outpatient HIV Care 
AIDS Patient Care and STDs  2010;24(3):159-164.
Abstract
Routine HIV screening is recommended by the Centers for Disease Control and Prevention (CDC), but it is unknown how well internal medicine residents are trained in HIV risk assessment, testing, counseling, and initial management of HIV patients. We sought to determine internal medicine residents' attitudes about HIV training and the factors that influence their HIV care performance utilizing a cross-sectional survey of 321 second- and third-year internal medicine residents from four programs in Baltimore, Boston, Detroit, and New York City between March and June 2006. Measurements included HIV care experience; attitudes, competency, and adequacy of HIV training; and basic HIV care performance and factors impacting performance. Two hundred twenty-three residents (69%) completed the survey. While 50% of residents reported over 30 HIV inpatient encounters in the past year, the majority of residents had limited outpatient exposure providing care for only 1–5 HIV outpatients. Managing HIV patients was rated an excellent educational opportunity by 89% of residents and 77% planned to care for HIV patients in the future. However, 39% stated that they did not feel competent to provide HIV outpatient care. Higher rates of residents reported deficiency in oupatient HIV training compared to outpatient non-HIV training (p < 0.05) or inpatient HIV training (p < 0.05). Residents reported substandard HIV risk assessment, testing, counseling, and initial management performance. Self-reported proficiency correlated with the number of HIV outpatients cared for and perceived training adequacy. Current residency training in HIV care remains largely inpatient-based and residents frequently rate HIV outpatient training as inadequate.
doi:10.1089/apc.2009.0302
PMCID: PMC2933560  PMID: 20214483
11.  Long-Term Combination Antiretroviral Therapy Is Associated with the Risk of Coronary Plaques in African Americans with HIV Infection 
AIDS Patient Care and STDs  2009;23(10):815-824.
Abstract
The aim of the study was to assess whether long-term antiretroviral therapy (ART) is associated with the risk of coronary plaques in HIV-infected cardiovascularly asymptomatic African Americans. Between August 2003 and December 2007, 176 HIV-infected cardiovascularly asymptomatic African Americans were consecutively enrolled in an observational study investigating the effects of ART on subclinical atherosclerosis in Baltimore, Maryland. Computed tomography coronary angiography was performed to detect coronary plaques. The overall prevalence rate of coronary plaques was 30%. After adjusting for gender, total cholesterol, and cocaine use, logistic regression analysis revealed that exposure to ART for more than 18 months (adjusted odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.01, 4.79) was independently associated with the presence of coronary plaques. A higher HIV viral load was univariately associated with the presence of noncalcified plaques. Use of ART (>18 months) was independently associated with the presence of noncalcified plaques (adjusted OR: 7.61, 95% CI: 1.67, 34.7), whereas cocaine use (>15 years) was independently associated with the presence of calcified plaques (adjusted OR: 2.51, 95% CI: 1.11, 5.67). This study suggests that long-term exposure to ART may be associated with coronary plaques. Because long-term use of ART and HIV replication may be associated with the presence of noncalcified plaques, some of which may be more vulnerable to rupture, an intensive lifestyle intervention to reduce traditional risk factors for coronary artery disease (CAD) is ultimately vital to those who are on ART. This study also suggests that cocaine cessation is the single most effective strategy to prevent CAD in HIV-infected cocaine users.
doi:10.1089/apc.2009.0048
PMCID: PMC2761979  PMID: 19803679
12.  Long-term Combination Antiretroviral Therapy Is Associated with the Risk of Coronary Plaques in African Americans with HIV Infection 
AIDS patient care and STDs  2009;23(10):815-824.
The aim of the study was to assess whether long-term antiretroviral therapy (ART) is associated with the risk of coronary plaques in HIV-infected cardiovascularly asymptomatic African Americans. Between August 2003 and December 2007, 176 HIV-infected cardiovascularly asymptomatic African Americans were consecutively enrolled in an observational study investigating the effects of ART on subclinical atherosclerosis in Baltimore, Maryland. Computed tomography coronary angiography was performed to detect coronary plaques. The overall prevalence rate of coronary plaques was 30%. After adjusting for sex, total cholesterol, and cocaine use, logistic regression analysis revealed that exposure to ART for >18 months (adjusted OR: 2.20, 95% CI:1.01, 4.79) was independently associated with the presence of coronary plaques. A higher HIV viral load was univariately associated with the presence of noncalcified plaques. Use of ART (>18 months) was independently associated with the presence of noncalcified plaques (adjusted OR: 7.61, 95% CI: 1.67, 34.7), whereas cocaine use (>15 years) was independently associated with the presence of calcified plaques (adjusted OR: 2.51, 95% CI: 1.11, 5.67). This study suggests that long-term exposure to ART may be associated with coronary plaques. Because long-term use of ART and HIV replication may be associated with the presence of noncalcified plaques, some of which may be more vulnerable to rupture, an intensive lifestyle intervention to reduce traditional risk factors for coronary artery disease (CAD) is ultimately vital to those who are on ART. This study also suggests that cocaine cessation is the single most effective strategy to prevent CAD in HIV-infected cocaine users.
doi:10.1089/apc.2009.0048
PMCID: PMC2761979  PMID: 19803679
HIV infection; Antiretroviral Therapy; Coronary Plaques; Cocaine Use; Coronary CT angiography; African Americans
13.  Long-Term Cocaine Use and Antiretroviral Therapy Are Associated with Silent Coronary Artery Disease in African Americans with HIV Infection Who Have No Cardiovascular Symptoms 
Background
Long-term use of cocaine (⩾15 years) and antiretroviral therapy (ART) have been implicated in cardiovascular complications. Nevertheless, the individual and combined effects of ART and cocaine use on silent coronary artery disease have not been fully investigated.
Methods
Computed tomography coronary angiography was performed for 165 human immunodeficiency virus (HIV)–infected African American study participants aged 25–54 years in Baltimore, Maryland, with contrast-enhanced 64-slice multidetector computed tomography imaging.
Results
Significant (⩾50%) coronary stenosis was detected in 24 (15%) of 165 participants. The prevalence of significant stenosis among those who had used cocaine for ⩾15 years and had received ART for ⩾6 months was 42%. Exact logistic regression analysis revealed that long-term cocaine use (adjusted odds ratio, 7.75; 95% confidence interval, 2.26–31.2) and exposure to ART for ⩾6 months (adjusted odds ratio, 4.35; 95% confidence interval, 1.30–16.4) were independently associated with the presence of significant coronary stenosis. In addition, after controlling for confounding factors, both stavudine use for ⩾6 months or combivir use for ⩾6 months were independently associated with the presence of significant coronary stenosis.
Conclusions
Long-term exposure to ART may be associated with silent coronary artery disease; however, the magnitude of increased risk associated with ART was much lower than the risk associated with cocaine use or traditional risk factors. Cardiovascular monitoring and aggressive modification of cardiovascular risk factors are essential for reducing the risk of coronary artery disease in HIV-infected individuals. Extensive efforts should also be made to develop effective cocaine use cessation programs for HIV-infected cocaine users.
doi:10.1086/526782
PMCID: PMC2716694  PMID: 19641630
14.  Impact of Duty Hour Regulations on Medical Students’ Education: Views of Key Clinical Faculty 
Journal of General Internal Medicine  2008;23(7):1084-1089.
BACKGROUND
Teaching faculty have valuable perspectives on the impact of residency duty hour regulations on medical students.
OBJECTIVE
The objective of this study was to elicit faculty views on the impact of residency duty hour regulations on medical students’ educational experience on inpatient medicine rotations.
DESIGN AND PARTICIPANTS
We conducted a National Survey of Key Clinical Faculty (KCF) at 40 internal medicine residency programs affiliated with U.S. medical schools using a random sample stratified by National Institutes of Health funding and program size.
MEASUREMENTS
This study measures KCF opinions on the effect of duty hour regulations on students’ education.
RESULTS
Of 154 KCF targeted, 111 responded (72%). Fifty-two percent of KCF reported worsening in the overall quality of students’ education compared to just 2.7% reporting improvement (p < 0.001). In multivariate analysis adjusted for gender, academic rank, specialty, and years of teaching experience, faculty who spent ≥15 hours per week teaching were more likely to report worsening in medical students’ level of responsibility on inpatient teams [odds ratio (OR) 3.1; 95% confidence interval (CI) 1.3–7.6], ability to follow patients throughout hospitalization (OR 3.2; 95% CI 1.3–7.9), ability to develop working relationships with residents (OR 2.3; 95% CI 1.0–5.2), and the overall quality of students’ education (OR 3.3; 95% CI 1.4–8.1) compared to faculty who spent less time teaching.
CONCLUSION
Key clincal faculty report concerns about the impact of duty hour regulations on aspects of medical students’ education in internal medicine. Medical schools and residency programs should identify ways to ensure optimal educational experiences for students within duty hour requirements.
doi:10.1007/s11606-008-0532-1
PMCID: PMC2517919  PMID: 18612749
medical students; residents; duty hours; key clinical faculty; internal medicine
15.  Chronic CD4+ T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics▿  
Journal of Virology  2007;82(4):1870-1883.
The mechanism of CD4+ T-cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4+ T-cell activation. We assumed that the pathogenic process of excessive CD4+ T-cell activation would be reflected in the transcriptional profiles of activated CD4+ T cells. Here we demonstrate that the transcriptional programs of in vivo-activated CD4+ T cells from untreated HIV-positive (HIV+) individuals are clearly different from those of activated CD4+ T cells from HIV-negative (HIV−) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4+ T cells of untreated HIV+ individuals. Furthermore, we find an enrichment of proliferative and type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4+ T cells of untreated HIV+ individuals compared to those of HIV− individuals. We confirm these findings by examination of in vivo-activated CD4+ T cells. Taken together, these results suggest that activated CD4+ T cells from untreated HIV+ individuals are in a hyperproliferative state that is modulated by type I interferons. From these results, we propose a new model for CD4+ T-cell depletion during chronic HIV-1 infection.
doi:10.1128/JVI.02228-07
PMCID: PMC2258719  PMID: 18077723
16.  Update in HIV Care 
doi:10.1007/s11606-006-0035-x
PMCID: PMC1824734  PMID: 17356995
HIV; AIDS; antiretroviral
17.  Update in HIV Care 
doi:10.1007/s11606-006-0035-x
PMCID: PMC1824734  PMID: 17356995
HIV; AIDS; antiretroviral
18.  Residual Human Immunodeficiency Virus Type 1 Viremia in Some Patients on Antiretroviral Therapy Is Dominated by a Small Number of Invariant Clones Rarely Found in Circulating CD4+ T Cells†  
Journal of Virology  2006;80(13):6441-6457.
Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4+ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4+ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4+ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4+ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4+ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4+ T cells.
doi:10.1128/JVI.00591-06
PMCID: PMC1488985  PMID: 16775332
19.  Promotion Criteria for Clinician-educators 
OBJECTIVE
Department of medicine chairs have a critical role in the promotion of clinician-educators. Our primary objective was to determine how chairs viewed: 1) the importance of specific areas of clinician-educator performance in promotion decisions; and 2) the importance and quality of information on available measures of performance. A secondary objective was to compare the views of department chairs with those of promotion and tenure committee chairs.
METHODS
In October 1997, a questionnaire was mailed to all department chairs in the United States and Canada asking them to rate the importance of 11 areas of clinician-educators' performance in evaluating them for promotion. We also asked them to rate 36 measures of performance. We compared their responses to a similar 1996 survey administered to promotion committee chairs.
RESULTS
One hundred fourteen of 139 department chairs (82%) responded to the survey. When considering a clinician-educator for promotion, department chairs view teaching skills and clinical skills as the most important areas of performance, as did the promotion committee chairs. Of the measures used to evaluate teaching performance, teaching awards were considered most important and rated as a high-quality measure. When evaluating a clinician-educator's clinical skills, peer and trainee evaluation were considered as the most important measures of performance, but these were rated low in quality. Patient satisfaction and objective outcome measures also were viewed as important measures that needed improvement. Promotion committee chairs placed more emphasis on productivity in publications and external grant support when compared to department chairs.
CONCLUSION
It is reassuring that both department chairs and promotion committee chairs value teaching skills and clinical skills as the most important areas of a clinician-educator's performance when evaluating for promotion. However, differences in opinion regarding the importance of several performance measures and the need for improved quality measures may represent barriers to the timely promotion of clinician-educators.
doi:10.1046/j.1525-1497.2003.10425.x
PMCID: PMC1494922  PMID: 12950479
promotion criteria; clinician-educators; academic advancement
20.  Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1 
Journal of Virology  2004;78(4):1718-1729.
Human immunodeficiency virus type 1 (HIV-1)-infected individuals who develop drug-resistant virus during antiretroviral therapy may derive benefit from continued treatment for two reasons. First, drug-resistant viruses can retain partial susceptibility to the drug combination. Second, therapy selects for drug-resistant viruses that may have reduced replication capacities relative to archived, drug-sensitive viruses. We developed a novel single-cell-level phenotypic assay that allows these two effects to be distinguished and compared quantitatively. Patient-derived gag-pol sequences were cloned into an HIV-1 reporter virus that expresses an endoplasmic reticulum-retained Env-green fluorescent protein fusion. Flow cytometric analysis of single-round infections allowed a quantitative analysis of viral replication over a 4-log dynamic range. The assay faithfully reproduced known in vivo drug interactions occurring at the level of target cells. Simultaneous analysis of single-round infections by wild-type and resistant viruses in the presence and absence of the relevant drug combination divided the benefit of continued nonsuppressive treatment into two additive components, residual virus susceptibility to the drug combination and selection for drug-resistant variants with diminished replication capacities. In some patients with drug resistance, the dominant circulating viruses retained significant susceptibility to the combination. However, in other cases, the dominant drug-resistant viruses showed no residual susceptibility to the combination but had a reduced replication capacity relative to the wild-type virus. In this case, simplification of the regimen might still allow adequate suppression of the wild-type virus. In a third pattern, the resistant viruses had no residual susceptibility to the relevant drug regimen but nevertheless had a replication capacity equivalent to that of wild-type virus. In such cases, there is no benefit to continued treatment. Thus, the ability to simultaneously analyze residual susceptibility and reduced replication capacity of drug-resistant viruses may provide a basis for rational therapeutic decisions in the setting of treatment failure.
doi:10.1128/JVI.78.4.1718-1729.2004
PMCID: PMC369469  PMID: 14747537
21.  HIV Care and General Internal Medicine 
doi:10.1046/j.1525-1497.2001.016009638.x
PMCID: PMC1495258  PMID: 11556946
22.  Introduction of Evidence-based Medicine into an Ambulatory Clinical Clerkship 
Evidence-based medicine (EBM) has emerged has a critical clinical competency in the 21st century. Medical schools usually introduce students to critical appraisal in the preclinical years, but there have been few evaluated interventions in teaching EBM in the clinical years. We describe a strategy to encourage students to practice EBM during a required ambulatory medicine clerkship. During this clerkship, our students are required to submit an EBM report, which is prompted by an individual case, and structured with a 5-step approach. One small-group session is devoted to modeling this approach with a case of chest pain. Using a checklist to grade 216 consecutive EBM reports, we found that students were quite successful with the exercise, achieving on average 89.6% of possible checklist points. Students who followed the structure of the exercise closely were more likely to extend their discussions beyond that required and to suggest potential further areas of investigation or design.
doi:10.1046/j.1525-1497.2001.016004244.x
PMCID: PMC1495202  PMID: 11318925
medical education; medical student; evidence-based medicine; ambulatory clerkship

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